2 y chromosome: What Is XYY Syndrome? Symptoms, Causes, Diagnosis, Treatment, and Prevention
XYY Syndrome (for Parents) – Nemours Kidshealth
What Is XYY Syndrome?
XYY syndrome is a genetic condition found in males only. About 1 in 1,000 boys have it.
Boys with XYY syndrome — also known as 47,XYY — might be taller than other boys. Other symptoms can include problems with spoken language and processing spoken words, coordination problems, weaker muscles, hand tremors, and behavioral problems.
Most boys with XYY syndrome can grow up healthy, have normal sexual development and fertility, and lead productive lives.
Symptoms can vary greatly among boys. Depending on which symptoms a boy has and how severe they are, doctors may recommend various treatments.
What Causes XYY Syndrome?
Boys who have XYY syndrome are born with it. It’s called XYY because they have an extra Y
chromosomein most or all their cells.
Usually, a person has 46 chromosomes in each cell, divided into 23 pairs, which includes two sex chromosomes. Half the chromosomes are inherited from the father and the other half from the mother. The chromosomes contain genes, which determine an individual’s characteristics, such as eye color and height. Boys typically have one X chromosome and one Y chromosome, or XY, but boys with XYY syndrome have an extra Y chromosome, or XYY.
XYY syndrome is not caused by anything the parents did or did not do. The disorder is a random error in cell division. This error can happen before conception in the reproductive cells of the mother or the father, or early in the embryo’s development.
When the extra chromosome is the result of incorrect cell division early in the embryo’s development, a boy may have a mosaic form of XYY syndrome. This means some cells have an extra Y chromosome, but not all do. Boys with mosaic XYY syndrome usually have fewer symptoms.
What Are the Signs & Symptoms of XYY Syndrome?
Noticeable signs and symptoms of XYY syndrome can vary greatly. Some boys have no obvious signs, while others have mild symptoms. Occasionally, the disorder causes significant problems.
Boys with XYY syndrome may have some or all of these physical symptoms to some degree:
- taller than average height
- low muscle tone, or muscle weakness (called hypotonia)
- very curved pinky finger (called clinodactyly)
- widely spaced eyes (called hypertelorism)
Some boys also may have delayed development of their social, language, and learning skills. They also can have problems with reading and understanding math, and may have mild delays with coordination.
What Problems Can Happen?
Some boys with XYY syndrome may develop behavioral problems, such as ADHD, autism, temper tantrums, impulsivity, or defiant behavior. These problems might ease as they get older and reach adulthood. Otherwise, treatment can help manage these issues.
A small number of boys may have increased testicular size for their age, or have an increased risk for asthma and seizures.
How Is XYY Syndrome Diagnosed?
Many boys with XYY syndrome are healthy and have no obvious symptoms. So sometimes the condition isn’t diagnosed or is found when a doctor checks for a different issue.
Often, XYY syndrome is found because parents talked with a doctor about concerns with their son’s development. This can help boys receive a diagnosis early. Research has shown that early interventions and treatments are more effective.
To diagnosis XYY syndrome, doctors check a blood sample for the extra Y chromosome. Before birth, the condition may be found through
karyotype test(chromosomal analysis) or noninvasive prenatal testing (NIPT). NIPT is done on the fluid surrounding the fetus, tissue from the placenta, or the blood from the mother. After birth, doctors can make a diagnosis with a karyotype or with a
microarray test from the baby.
How Is XYY Syndrome Treated?
There’s no cure for XYY syndrome, but treatments can help with specific symptoms.
Finding services early is important and can greatly increase their ability to help boys live a healthier, more productive life. Options vary greatly depending on how old a boy is at the time of his diagnosis, whether he has noticeable symptoms, and the severity of those symptoms.
Treatments can include:
Regular doctor visits. At periodic visits, a doctor can monitor a boy’s development for delays, social and language disabilities, or health problems and treat these promptly.
Educational support services. Educational support can teach boys ways to keep pace in school. Some might be eligible for an individualized educational program (IEP) or 504 education plan, which are designed to help children with special needs.
Early intervention services. It can be very helpful and often more effective for a boy to have speech, occupational, physical, or developmental therapy in the early months of life or as soon as concerns are found.
Speech therapy and physical therapy can improve a boy’s speaking, reading, and writing skills and help increase strength and coordination. Occupational therapy and behavioral therapy can help them develop more confidence and interact better with other children.
Counseling. The whole family can benefit from counseling to better understand XYY syndrome and help a boy who has it to live a productive life.
Early inventions should be considered at infancy for physical therapy, at 15 months for speech delay, at 1st grade for reading and learning issues, and at 3rd grade for anxiety or depression.
What Else Should I Know?
Boys with XYY syndrome can develop speech, learning, or social challenges at a young age. This can make them more likely to have low self-esteem and lead to school or social problems.
If your son has trouble making friends or struggles in school, talk to your doctor or the principal or school counselor. Counseling and therapy can teach your son practical skills to help him make friends and feel more confident in school, and educational services can help him do well in school.
Talk to your doctor if you have any concerns about your son’s physical and emotional development.
Despite physical differences and other problems, with the right medical care, early intervention, and ongoing support, a boy with XYY syndrome can lead a normal, healthy, and productive life.
What is Superman Syndrome?
Superman syndrome, also known as 47, XYY, is a condition classified as a chromosomal aneuploidy (which is an abnormality in chromosome structure and/or number) in which males have an additional Y chromosome.
Image Credit: Rost9 / Shutterstock.com
The normal male sex chromosomes are XY; in the case of Superman syndrome, males possess one additional Y chromosome in addition to the paternally inherited Y chromosome. As with other sex-linked aneuploidies, which describe sex chromosomal arrangements that differ from the normal 46, XX in females and 46, XY in males, this congenital condition is compatible with life.
The term ‘superman’ refers to the presence of the additional male-defining Y chromosome and affects approximately 1 in every 850 males. The 47, XYY karyotype, which describes the number and appearance of the chromosomes in a cell, is associated with neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD).
The 47, XYY condition is the most common of all aneuploidies and has generated much scientific interest given early research, which suggested an association between this karyotype and the likelihood of violent crimes. Later research, which examined the association between violent crime and the condition in larger cohorts, debunked this. Instead, these studies uncovered the stronger correlation between the risk of neurodevelopmental difficulties and the possession of the 47, XYY karyotype.
The hallmarks of Superman Syndrome
A present, the neurodevelopmental phenotype of XYY is associated with a lower-than-average intelligence quotient (IQ), impediments in speech and language, learning difficulties, poor performance in school, difficulties with social interaction, and poor attention span.
The deficit in IQ is quantifiably lowered by 10 points on average, according to studies examining cognitive ability in XYY males. This deficit primarily affects the verbal processing centers in the brain and translates to language delays, and associated language development handicap in birth cohorts (in which XYY is diagnosed at birth) as well as clinical cohorts (diagnosis later in life).
With regard to difficulties in academic performance, XYY individuals find difficulty reading and show poor adaptive functioning. Adaptive functioning describes a person’s ability to function interpersonally in social situations. The challenge faced by XYY is surprising, as social function is not associated with lowered IQ.
However, consistent with reduced IQ and social functioning, XYY show statistically greater than average rates of intellectual disability relative to the general population. Most notable impairments in adaptive functioning include neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).
The association between XYY and ASD is an area of active research, motivated by observing a notable difference between the ratio of ASD in children possessing the normal 46, XY or XX and those with 47, XYYX. In a recent study, the rate of ASD in males with XYY chromosomes was determined at 14%. Other less prevalent neurodevelopmental conditions associated with XYY include mood and anxiety disorder, oppositional defiance disorder, obsessive-compulsive spectrum disorder, and tic disorder.
General genetic characteristics of 47, XYY
The aneuploidy that is associated with XYY arises when a male receives an additional Y chromosome of paternal origin, resulting in a total chromosomal count of 47. The error that leads to this genotype arises from meiotic divisions in which non-disjunction, in which pairs of homologous chromosomes fail to separate during meiosis, the process of sex chromosome formation.
These structural disorders may be visible at the level of the light microscope i. e., cytogenetically visible; in cases where the structural changes are slightly more subtle, these changes are visible at the sub-microscopic level. The most prevalent structural abnormality is a balanced translocation – here, almost all or part of a chromosome is physically attached to another.
In the chromosome that remains ‘balanced’, genetic information is neither lost nor gained, and this chromosome is not usually associated with any phenotype unless the breakpoint (the point at which the chromosomes separate) is located at a gene. In this case, the chromosomes do not segregate normally, with the fetus at risk of losing or gaining genetic information.
These resultant fetuses are generally incapable of survival, can cause recurrent miscarriage. However, several will proceed to term with a number of mental and physical abnormalities.
Bardesley, M.D. et al. 47,XYY Syndrome: Clinical Phenotype and Timing of Ascertainment. J Pediatr. (2014) doi: 10. 1016/j.jpeds.2013.05.037
Geerts, M. et al. The XYY syndrome: a follow-up study on 38 boys. Genet Couns (2003) https://www.ncbi.nlm.nih.gov/pubmed/14577671
Schiavi, R.C. et al. Sex chromosome anomalies, hormones, and aggressivity. Arch Gen Psychiatry. 1984 doi: 10.1001/archpsyc.1984.01790120097012
Walzer, S. et al. Cognitive and behavioral factors in the learning disabilities of 47,XXY and 47,XYY boys. Birth Defects. Orig Artic Ser. (1990) https://www.ncbi.nlm.nih.gov/pubmed/2090328
Bishop, D.A. et al. Autism, language and communication in children with sex chromosome trisomies. Arch Dis Child. (2010) doi: 10.1136/adc.2009.179747
Klinefelter syndrome – NHS
Klinefelter syndrome (sometimes called Klinefelter’s, KS or XXY) is where boys and men are born with an extra X chromosome.
Chromosomes are packages of genes found in every cell in the body. There are 2 types of chromosome, called the sex chromosomes, that determine the genetic sex of a baby. These are named either X or Y.
Usually, a female baby has 2 X chromosomes (XX) and a male has 1 X and 1 Y (XY). But in Klinefelter syndrome, a boy is born with an extra copy of the X chromosome (XXY).
The X chromosome is not a “female” chromosome and is present in everyone. The presence of a Y chromosome denotes male sex.
Boys and men with Klinefelter syndrome are still genetically male, and often will not realise they have this extra chromosome, but occasionally it can cause problems that may require treatment.
Klinefelter syndrome affects around 1 in every 660 males.
Symptoms of Klinefelter syndrome
Klinefelter syndrome does not usually cause any obvious symptoms early in childhood, and even the later symptoms may be difficult to spot.
Many boys and men do not realise they have it.
Possible features, which are not always present, may include:
- in babies and toddlers – learning to sit up, crawl, walk and talk later than usual, being quieter and more passive than usual
- in childhood – shyness and low self-confidence, problems with reading, writing, spelling and paying attention, mild dyslexia or dyspraxia, low energy levels, and difficulty socialising or expressing feelings
- in teenagers – growing taller than expected for the family (with long arms and legs), broad hips, poor muscle tone and slower than usual muscle growth, reduced facial and body hair that starts growing later than usual, a small penis and testicles, and enlarged breasts (gynaecomastia)
- in adulthood – inability to have children naturally (infertility) and a low sex drive, in addition to the physical characteristics mentioned above
Health issues in Klinefelter syndrome
Most boys and men with Klinefelter syndrome will not be significantly affected and can live normal, healthy lives.
Infertility tends to be the main problem, although there are treatments that can help.
But men with Klinefelter syndrome are at a slightly increased risk of developing other health problems, including:
These problems can usually be treated if they do occur and testosterone replacement therapy may help reduce the risk of some of them.
Causes of Klinefelter syndrome
Klinefelter syndrome is caused by an additional X chromosome.
This chromosome carries extra copies of genes, which interfere with the development of the testicles and mean they produce less testosterone (male sex hormone) than usual.
The extra genetic information may either be carried in every cell in the body or it may only affect some cells (known as mosaic Klinefelter syndrome).
Klinefelter syndrome is not directly inherited – the additional X chromosome occurs as a result of either the mother’s egg or the father’s sperm having the extra X chromosome (an equal chance of this happening in either), so after conception the chromosome pattern is XXY rather than XY.
This change in the egg or sperm seems to happen randomly. If you have a son with the condition, the chances of this happening again are very small.
But the risk of a woman having a son with Klinefelter syndrome may be slightly higher if the mother is over 35 years of age.
Testing for Klinefelter syndrome
See your GP if you have concerns about your son’s development or you notice any troubling symptoms of Klinefelter syndrome in yourself or your son.
Klinefelter syndrome is not necessarily anything serious, but treatment can help reduce some of the symptoms if necessary.
In many cases, it’s only detected if a man with the condition undergoes fertility tests.
Your GP may suspect Klinefelter syndrome after a physical examination and may suggest sending off a sample of blood to check reproductive hormone levels.
The diagnosis can be confirmed by checking a sample of blood for the presence of the extra X chromosome.
Treatments for Klinefelter syndrome
There’s no cure for Klinefelter syndrome, but some of the problems associated with the condition can be treated if necessary.
Possible treatments include:
- testosterone replacement therapy
- speech and language therapy during childhood to help with speech development
- educational and behavioural support at school to help with any learning difficulties or behaviour problems
- occupational therapy to help with any co-ordination problems associated with dyspraxia
- physiotherapy to help build muscle and increase strength
- psychological support for any mental health issues
- fertility treatment – options include artificial insemination using donor sperm or possibly intracytoplasmic sperm injection (ICSI), where sperm removed during a small operation are used to fertilise an egg in a laboratory
- breast reduction surgery to remove excess breast tissue
Testosterone replacement therapy (TRT)
TRT involves taking medicines containing testosterone. It can be taken in the form of gels or tablets in teenagers, or given as gel or injections in adult men.
TRT may be considered once puberty begins and may help with the development of a deep voice, facial and body hair, an increase in muscle mass, reduction in body fat, and improvement in energy. There is also evidence that it can help with learning and behavioural problems.
You should see a specialist in children’s hormones (a paediatric endocrinologist) at this time.
Long-term treatment during adulthood may also help with several other problems associated with Klinefelter syndrome – including osteoporosis, low mood, reduced sex drive, low self-esteem and low energy levels – although it cannot reverse infertility.
More information and support
If you or your son has been diagnosed with Klinefelter syndrome, you might find it useful to find out more about it and get in touch with others affected by it.
The following websites may be able to help:
Page last reviewed: 20 May 2019
Next review due: 20 May 2022
Klinefelter syndrome – Symptoms and causes
Klinefelter syndrome is a genetic condition that results when a boy is born with an extra copy of the X chromosome. Klinefelter syndrome is a genetic condition affecting males, and it often isn’t diagnosed until adulthood.
Klinefelter syndrome may adversely affect testicular growth, resulting in smaller than normal testicles, which can lead to lower production of testosterone. The syndrome may also cause reduced muscle mass, reduced body and facial hair, and enlarged breast tissue. The effects of Klinefelter syndrome vary, and not everyone has the same signs and symptoms.
Most men with Klinefelter syndrome produce little or no sperm, but assisted reproductive procedures may make it possible for some men with Klinefelter syndrome to father children.
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Signs and symptoms of Klinefelter syndrome vary widely among males with the disorder. Many boys with Klinefelter syndrome show few or only mild signs. The condition may go undiagnosed until adulthood or it may never be diagnosed. For others, the condition has a noticeable effect on growth or appearance.
Signs and symptoms of Klinefelter syndrome also vary by age.
Signs and symptoms may include:
- Weak muscles
- Slow motor development — taking longer than average to sit up, crawl and walk
- Delay in speaking
- Problems at birth, such as testicles that haven’t descended into the scrotum
Boys and teenagers
Signs and symptoms may include:
- Taller than average stature
- Longer legs, shorter torso and broader hips compared with other boys
- Absent, delayed or incomplete puberty
- After puberty, less muscle and less facial and body hair compared with other teens
- Small, firm testicles
- Small penis
- Enlarged breast tissue (gynecomastia)
- Weak bones
- Low energy levels
- Tendency to be shy and sensitive
- Difficulty expressing thoughts and feelings or socializing
- Problems with reading, writing, spelling or math
Signs and symptoms may include:
- Low sperm count or no sperm
- Small testicles and penis
- Low sex drive
- Taller than average height
- Weak bones
- Decreased facial and body hair
- Less muscular compared with other men
- Enlarged breast tissue
- Increased belly fat
When to see a doctor
See a doctor if you or your son has:
- Slow development during infancy or boyhood. Delays in growth and development can be the first sign of a number of conditions that need treatment — including Klinefelter syndrome. Though some variation in physical and mental development is normal, it’s best to check with a doctor if you have any concerns.
- Male infertility. Many men with Klinefelter syndrome aren’t diagnosed with infertility until they realize they’re unable to father a child.
Klinefelter syndrome occurs as a result of a random error that causes a male to be born with an extra sex chromosome. It isn’t an inherited condition.
Humans have 46 chromosomes, including two sex chromosomes that determine a person’s sex. Females have two X sex chromosomes (XX). Males have an X and a Y sex chromosome (XY).
Klinefelter syndrome can be caused by:
- One extra copy of the X chromosome in each cell (XXY), the most common cause
- An extra X chromosome in some of the cells (mosaic Klinefelter syndrome), with fewer symptoms
- More than one extra copy of the X chromosome, which is rare and results in a severe form
Extra copies of genes on the X chromosome can interfere with male sexual development and fertility.
Klinefelter syndrome stems from a random genetic event. The risk of Klinefelter syndrome isn’t increased by anything a parent does or doesn’t do. For older mothers, the risk is higher but only slightly.
Klinefelter syndrome may increase the risk of:
- Anxiety and depression
- Social, emotional and behavioral problems, such as low self-esteem, emotional immaturity and impulsiveness
- Infertility and problems with sexual function
- Weak bones (osteoporosis)
- Heart and blood vessel disease
- Breast cancer and certain other cancers
- Lung disease
- Metabolic syndrome, which includes type 2 diabetes, high blood pressure (hypertension), and high cholesterol and triglycerides (hyperlipidemia)
- Autoimmune disorders such as lupus and rheumatoid arthritis
- Tooth and oral problems that make dental cavities more likely
- Autism spectrum disorder
A number of complications caused by Klinefelter syndrome are related to low testosterone (hypogonadism). Testosterone replacement therapy reduces the risk of certain health problems, especially when therapy is started at the beginning of puberty.
Sept. 21, 2019
Kaiser Permanente Genetics Northern California
What is XYY syndrome?
How common is XYY?
What causes XYY?
How is XYY diagnosed?
Can XYY be diagnosed during pregnancy?
How is XYY treated?
Where can I get more information about XYY?
What is XYY syndrome?
XYY syndrome (XYY) is a genetic condition in males that may include taller height, a slightly larger head size, and lower muscle tone. However, the features in this condition tend to fall in the normal range for males, so most individuals with XYY are not diagnosed.
Medical concerns in XYY
It is unclear if there are special medical concerns in individuals with XYY. Some studies suggest there could be a slightly higher rate of seizures and tremors.
Learning and behavior in XYY
Most children with XYY have IQ scores that fall in the average range or slightly below average, but there is a wide range of learning abilities. Some children have delays in language development or reading skills. Behavior concerns may include attention problems and hyperactivity (ADHD), autism, and difficulty with social skills.
How common is XYY?
It is estimated that one in every 1000 newborn boys has XYY.
What causes XYY?
XYY syndrome is caused by an extra chromosome. Individuals with XYY have one X chromosomes and two Y chromosomes, instead of the usual pair of male sex chromosomes (one X and one Y). This chromosome arrangement is called 47,XYY. XYY happens as a random event when a sperm is being formed and is not inherited.
How is XYY diagnosed?
The diagnosis is usually made by a blood test that shows an extra Y chromosome in a male. XYY is rarely diagnosed at birth since babies with this condition look like other babies. Chromosome testing may be offered for children with learning delays or autistic behaviors.
Can XYY be diagnosed during pregnancy?
XYY can be diagnosed during pregnancy by testing a DNA sample from the developing baby. The sample can be obtained either by a chorionic villus sampling (CVS) or amniocentesis procedure.
One prenatal screening test, NIPT, can identify pregnancies that have a higher chance for XYY. More testing is needed to confirm the diagnosis.
How is XYY treated?
Health care for individuals with XYY is based on symptoms. Some children with XYY may benefit from early intervention programs to support learning. Medication may be considered for attention problems.
Where can I get more information about XYY syndrome?
Genetics Home Reference: XYY syndrome – General information about XYY provided as a service of the U. S. National Library of Health. Links to related sites are included on the page.
The Association for X and Y Chromosome Variations (AXYS) – National support organization for those affected by one or more extra sex chromosome.
Last updated: January 17, 2018
Reviewed by: Kimberly Barr, LCGC
Karyotype 47,XYY – an overview
Sex Chromosome Abnormalities
Some genetic disorders are not caused by mutations, but rather stem from the failure of sex chromosomes to properly separate during gamete formation – a process called nondysjunction. This will lead to numerical abnormalities, in which individuals have more than two sex chromosomes (either X or Y) or lack one copy. In addition, a chromosome may be present but functionally faulty. Unlike those with autosomal abnormalities (i.e., Down syndrome), affected individuals usually do not suffer global mental retardation. Instead, sex chromosome abnormalities often lead to learning disabilities and difficulty in specific cognitive domains. The most common types of cases are XYY syndrome, Klinefelter syndrome, and Turner syndrome (TS).
XYY males possess a trisomy of the sex chromosomes instead of the normal two. Most XYY males appear physically normal (aside from taller stature) and do not experience unusual deficits. However, there may be an increased risk of learning disorders and language problems. Additionally, there was early speculation that XYY males are more prone to aggression and criminal behavior, but this view was made obsolete in 1976. A study by Herman Witkin and colleagues showed that higher rates of XYY males in prison populations could be explained by lower intelligence rather than higher aggression or violence.
Some males possess an extra copy of the X chromosome. These XXY males exhibit Klinefelter syndrome. Unlike males with the XYY karyotype, Klinefelter males are usually sterile and often possess a variety of physical anomalies. Klinefelter boys tend to exhibit selective deficits in reading and language skills. Arithmetic skills may also be compromised, but visuospatial skills are remarkably intact. This often results in a large discrepancy between verbal intelligence quotients (IQ) and performance IQ.
One conclusion is that boys with sex chromosome abnormalities manifest a cognitive profile exaggerative of typical males. That is, delayed language skills tend to be coupled with normal visuospatial abilities. This observation is useful because it may shed light on disorders that are genetically more elusive (i.e., dyslexia, autism, stuttering). Interestingly, TS girls exhibit the opposite profile.
Girls with TS have only one intact X chromosome. Their second copy is a nonfunctional stub or is altogether missing. In over two-thirds of cases, it is the X-chromosome of paternal origin that is missing. The girls possess extremely short stature and a variety of medical problems. However, their condition often goes unnoticed until adolescence, when it is found that they are not developing secondary sexual characteristics. In terms of academic performance, they generally have verbal skills in the normal range but show deficits in spatial skills and mathematical problem solving.
This cognitive profile has attracted interest because it refutes hypotheses that superior visuospatial skills are X-linked recessive. However, females with TS also experience gonadal dysgenesis, which causes the ovaries to degenerate and thwart all secretion of hormones. Perhaps optimal spatial intelligence results from the interaction of sex steroids with genetic loci on the X chromosome. In 2003, a group led by Judith Ross evaluated that possibility by experimentally treating TS girls with androgen replacement. Surprisingly, girls who received androgen did not show increases in spatial cognition, but did show improvement in working memory.
Finally, some investigators have drawn a link between autism and TS, noting that the risk of autism is 200-fold in females with TS. Autism is present only among TS girls who inherited an intact X chromosome from their mother; no cases of autism are observed among those who possess a paternally derived X chromosome. David Skuse and colleagues have argued that genetic imprinting (i.e., different gene expression depending on which parent transmitted it) might explain the male vulnerability to autism, insomuch that superior social–emotional processing is associated with an X chromosome of paternal origin.
Chromosomal Variants in Klinefelter Syndrome – FullText – Sexual Development 2011, Vol. 5, No. 3
Klinefelter syndrome (KS) describes the phenotype of the most common sex chromosome abnormality in humans and occurs in one of every 600 newborn males. The typical symptoms are a tall stature, narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, absent spermatogenesis, normal to moderately reduced Leydig cell function, increased secretion of follicle-stimulating hormone, androgen deficiency, and normal to slightly decreased verbal intelligence. Apart from that, amongst others, osteoporosis, varicose veins, thromboembolic disease, or diabetes mellitus are observed. Some of the typical features can be very weakly pronounced so that the affected men often receive the diagnosis only at the adulthood by their infertility. With a frequency of 4%, KS is described to be the most common genetic reason for male infertility. The most widespread karyotype in affected patients is 47,XXY. Apart from that, various other karyotypes have been described, including 46,XX in males, 47,XXY in females, 47,XX,der(Y), 47,X,der(X),Y, or other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, and 49,XXXXY). The focus of this review was to abstract the different phenotypes, which come about by the various karyotypes and to compare them to those with a ‘normal’ KS karyotype. For that the patients have been divided into 6 different groups: Klinefelter patients with an additional isochromosome Xq, with additional rearrangements on 1 of the 2 X chromosomes or accordingly on the Y chromosome, as well as XX males and true hermaphrodites, 47,XXY females and Klinefelter patients with other numeric sex chromosome abnormalities. In the latter, an almost linear increase in height and developmental delay was observed. Men with an additional isochromosome Xq show infertility and other minor features of ‘normal’ KS but not an increased height. Aside from the infertility, in male patients with other der(X) as well as der(Y) rearrangements and in XXY women no specific phenotype is recognizable amongst others due to the small number of cases. The phenotype of XX males depends on the presence of SRY (sex-determining region Y) and the level of X inactivation at which SRY-negative patients are generally rarely observed.
© 2011 S. Karger AG, Basel
Klinefelter syndrome (KS) was first described by Harry F. Klinefelter in 1942 [Klinefelter et al., 1942]. He reported 9 men with testicular abnormalities who failed to produce sperm and had gynecomastia. In 1959, this was found to be the result of an additional X chromosome [Jacobs and Strong, 1959]. About 80% of KS patients show a 47,XXY karyotype, 20% have other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, 49,XXXXY), 46,XY/47,XXY mosaicism, or structurally abnormal sex chromosomes [Lanfranco et al., 2004].
In approximately half of the Klinefelter cases the aberrant X chromosome is thought to be paternally derived, and recent evidence suggests that it may be related to advancing paternal age, although this is controversial [Jacobs et al., 1988; Lowe et al., 2001]. With a frequency of 1 out of 600 newborn males KS is described to be the most common sex chromosome abnormality [Bojesen and Gravholt, 2007]. Affected patients are characterized by an increase of the body height of about 6.5 cm, narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, absent spermatogenesis, normal to moderately reduced Leydig cell function, increased secretion of follicle-stimulating hormone (FSH), androgen deficiency, and normal to slightly decreased verbal intelligence [Bojesen and Gravholt, 2007; Wikstrom and Dunkel, 2008]. Apart from that, amongst others, osteoporosis [van den Bergh et al., 2001], varicose veins, thromboembolic disease [Igawa and Nishioka, 2003], or diabetes mellitus [Ota et al., 2002] are observed. KS is the most frequent genetic cause of male infertility, and is found in 11% of azoospermic men and 4% of infertile men [Wikstrom and Dunkel, 2008]. In most of the cases KS is not diagnosed before puberty and even in adulthood it was estimated that only a fourth of affected males receive diagnosis, mostly by their infertility [Bojesen and Gravholt, 2007], because in many cases the phenotype is not as distinct as described above.
If somebody has an additional X chromosome, there is an excess of X-chromosomal genes. Normally 1 of the 2 X chromosomes in a female is inactivated, but it has been shown that in total, about 15% of X-linked genes escape inactivation [Carrel and Willard, 2005]. The same applies for KS patients and, therefore, it is very likely that these genes are responsible for most of the KS features.
Over the last almost 50 years there have been reported many cases of KS patients with a different karyotype than 47,XXY. These variants show, amongst others, a 47,X,der(X),Y karyotype, a 47,XX,der(Y) karyotype, an additional isochromosome Xq, as well as translocations or deletions involving one of the sex chromosomes. Apart from that there have been reported a lot of male cases with a 46,XX karyotype as well as women with a 47,XXY chromosome complement. In addition to all these patients with variations on the sex chromosomes, male KS patients with 2 X and 1 Y chromosomes and an additional rearrangement on one or more autosomal chromosomes have been described.
In this review we focused on the different genetic variants of the sex chromosomes in KS patients. Therefore, we attended to male patients with 2 or more X chromosomes and women with a 47,XXY karyotype. The aim of the review is to summarize the diverse phenotypes of these different variants of KS and to compare them to that of the classical 47,XXY KS patients. For our search we used 2 different databases: First PubMed using the following search terms: ‘Klinefelter’ AND ‘Syndrome’; ‘Klinefelter’ AND ‘Isochromosome X’; ‘46 XX’ AND ‘Male’; ‘47 XXY’ AND ‘Female’; ‘48 XXYY’; ‘48 XXXY’ and ‘49 XXXXY’ and second for the KS cases with derivative X or Y chromosomes the online database of the Jena University Hospital, Institute of Human Genetics, Jena (Germany). All searches were restricted to articles in English and German. We were looking exclusively for studies in which additional aberrations on the sex chromosomes were described. Articles on additional autosomal chromosomes or 47,XXY/46,XY karyotypes were excluded. For 46,XX males and 47,X,der(X),Y patients we included only SRY (sex-determining region Y) and XIST– (X (inactive)-specific transcript) positive patients or those where the breakpoints were obviously distal to the XIST location.
In the end we found more than 300 articles of KS variant patients at which most of the studies describe KS patients with other numeric sex chromosome abnormalities and XX males. Much of the literature was published between the 60s and 80s of the last century. In these cases the used ISCN nomenclature differs from the current version. To prevent misinterpretation or even adulteration of the original karyotypes, we always took over the karyotypes as indicated in the original literature.
Klinefelter Patients with an Additional Isochromosome Xq
The prevalence of the Klinefelter variant with an additional isochromosome Xq is calculated to be between 0.3–0.9% in males with a KS phenotype [Arps et al., 1996]. The first study of a 47,X,i(Xq),Y male was reported in 1969 [Zang et al., 1969]. Apart from that, to our knowledge, 24 further cases of isochromosome Xq have been reported so far [Demirhan et al., 2009]. Most of them described a monocentric isochromosome. The clinical and laboratory data on these cases are summarized in table 1. The patients show a nearly similar phenotype with characteristic features such as infertility, elevated plasma luteinizing hormone (LH) and FSH levels, low or normal testosterone levels, sometimes gynecomastia, normal to reduced body height, and a normal to slightly reduced intelligence level [Demirhan et al. , 2009]. Most of the literature indicated that the normal height is due to the presence of only one Xp carrying the growth gene SHOX (short stature homeobox-containing gene) [Richer et al., 1989; Stemkens et al., 2007] and other putative Xp-specific growth genes [Rao et al., 1997]. The observation of increased body height in a KS patient with an isodicentric X (pter→q22::q22→pter), with 3 copies of Xp and one distal part of Xq, is in agreement with this theory [Zelante et al., 1991].
Clinical features in 25 patients with KS and an additional isochromosome Xq sorted by the year of publication
Zang et al.  described the origin of an additional isochromosome Xq as an unusual event, because it would require a double error during meiosis. Arps et al.  proposed that the most probable origin of an additional isochromosome Xq is a misdivision of the centromere or a sister-chromatid exchange of one X chromosome. Höckner et al.  investigated a male patient with a 47,X,idic(X)(p11. 1),Y karyotype and found loss of heterozygosity for all informative Xq markers on the isochromosome and the presence of the other maternal allele on the normal homolog in each case of maternal heterozygosity. These results are in line with a maternal origin of a true dicentric isochromosome and not a maternal Xq/Xq translocation, and most likely postzygotic formation subsequent to a nondisjunction in maternal meiosis II [Höckner et al., 2008].
Klinefelter Patients with Additional Aberrations on One of the Two X Chromosomes
In the literature, only 5 cases with a 47,X,der(X),Y karyotype have been described. All of the cases were reported before 1981. Therefore, there is only little information about these rearrangements. The clinical and laboratory data on these cases are summarized in table 2. The first case showing such a karyotype was reported by Nielsen who described a male KS patient with terminal deleted X chromosome mosaic (10% normal 46,XY cells) [Nielsen, 1966]. At the age of 54 years, the man was just 160 cm tall and his whole body hair was scanty. He did not show gynecomastia, his penis was of normal size, and his testes were soft and measured 10 mm from pole to pole. His personality was described as childish and primitive and in comparison with ‘normal’ Klinefelter patients he showed more marked personality defects and his sexual activity was more pronounced. The sex chromatin percentage in buccal smear was 14% which is less than usually found in patients with KS. The decreased body height in the man, stands, because of his 2 Xp arms, in contrast to the hypothesis about the relevance of the number of SHOX gene copies, but it should be mentioned that Nielsen et al. published the case in 1966 and it is not possible to control the correctness of the karyotype.
Clinical features in 5 male patients with KS and a 47,XY,der(X) karyotype sorted by the year of publication
Chandra et al.  also reported a male patient with a 47,XXq-Y karyotype. A little less than half of the long arm appears to have been deleted from one of the X chromosomes. One sex chromatin body could be seen in 40–60% of the examined cells from hair roots and buccal mucosa. The patient was described as a dull-looking boy with rather a large build for his age and bilateral gynecomastia. His body hair had a feminine distribution and the testes were small and soft. All these symptoms resemble to those of normal KS patients and are partly identical to those of Nielsen’s case. The differences between these 2 cases are the gynecomastia and the body height, which supports the assertion of the SHOX gene hypothesis. However, it should be mentioned that Chandra et al.  described a boy of unknown age and Nielsen  a 54-year-old man.
Patil et al.  reported a case of a 19-year-old KS patient with gynecomastia, small testes, and azoospermia. The analysis of the chromosomes showed a deletion of parts of the long arm of the X chromosome with the breakpoint in q22. The authors interpreted the karyotype as 47,X,del(X)(pter→q22:),Y. Growth, weight and intellectual development were normal. Just the FSH and LH levels were increased. These symptoms were consistent with those reported in the case by Chandra et al. . Patil et al.  suggested that the region q11→22 might be associated with the phenotype of the KS, but this was revised in the same year by Fryns. He described a case of a 30-year-old male with completely normal phenotype without gynecomastia and normal sexual development [Fryns, 1981]. Both testes were small and sperm analysis revealed azoospermia. According to the study, his testosterone and LH levels were normal but FSH levels were elevated. The karyotype was 47,XY,+del(Xp11). Buccal smear analysis showed a small Barr body in 20% of the cells.
In comparison, we can say that a terminal deletion of the X chromosome shows a nearly similar phenotype to ‘normal’ KS. Just the body height differs from the typical KS phenotype and is normal to slightly reduced in the patients. The only reported case of a del(Xp) differs from all the other cases and did not even show affinity to the cases with an additional isochromosome Xq.
Klinefelter Patients with Additional Aberrations on the Y Chromosome
Eleven cases of KS patients with a 47,XX,der(Y) karyotype were found, but only 7 of them were described in detail (table 3). As the individual cases differ greatly from each other, we must consider them separately.
Clinical features in 11 male patients with KS and a 47,XX,der(Y) karyotype sorted by the year of publication
The most recent case we found was reported in 2009. The group presented a case of an unborn boy with a 47,XX,mar(Y) karyotype [Sheth et al., 2009]. Using different FISH clones for the SRY gene and for the centromeric and the subtelomeric region of the Y chromosome they found the presence of a neocentric inv dup (Y)(pter→Yp11.2::Yp11.2→pter). Spinner et al.  presented a case of a newborn infant with ovotesticular disorder of sex development and sex chromosome mosaicism. The karyotype was defined as 46,XXr(Y)/46,XX. The patient showed ambiguous genitalia and a micropenis. After an exploratory laparotomy the right gonad could be identified as an ovotestis and the left gonad as an undescended dysgenetic testis and a uterus lacking endothelial uterine glands. The r(Y) chromosome was transmitted via ICSI from the oligospermic but otherwise unremarkable father to the child. Apart from this article we found another one which described a case of an additional r(Y) chromosome [Weimer et al., 2006]. The patient showed signs of KS including gynecomastia, decreased body hair, hypergonadotropic hypogonadism, learning difficulties, an increased value of FSH, and a decreased value of testosterone. His sex development was male, consistent with the presence of the SRY locus on the r(Y) chromosome. At the age of 15 years, the boy presented with a mild overgrowth (182 cm), obesity (121 kg), and a slight outsized head circumference (59 cm). The karyotype was described as 48,XX,r(Y),+r(8)/ 47,XX,+r(Y)/47,XX,r(8)/46,XX. In 2006, a case of a 24-year-old man with a KS karyotype and an additional microdeletion on the Y chromosome was presented [Samli et al. , 2006]. The man was infertile and showed abnormally high LH and FSH levels but a lower testosterone level than usual. The group found a deletion in the AZFa region on the Y chromosome. The phenotype of the patient did not differ from those of KS patients without microdeletions in this region. Microdeletions in AZFa are often associated with Sertoli-cell-only syndrome and azoospermia and with a frequency of 1–2% they are one of the most frequent reasons of spermatogenetic failure and infertility [Poongothai et al., 2009].
An interesting case about a 31-year-old male patient with an in part Klinefelter phenotype and an isodicentric Y-chromosome was reported by Heinritz et al. . The karyotype was indicated as 47,XX,+idic(Y)(q12). The man showed a tall stature, unproportionally long slender legs, a normal male body hair patterning, but slightly reduced growth of his facial hair, gynecomastia, genitalia with hypoplastic, soft testes, and a small penis. The behavior of the man was described as aggressive with rapid alterations of the mood and a naive and inappropriate social performance. The LH and FSH levels were increased, but testosterone levels were lower than normal [Heinritz et al., 2005]. Normally, psychological and behavioral problems like violence, aggressiveness, and a low IQ are the main features of males with 48,XXYY and are very untypical for KS patients [Heinritz et al., 2005]. In earlier studies, the presence of an additional Y chromosome, as in men with 47,XYY, was discussed to be related to personality problems and mainly a quick-tempered behavior, but the molecular basis for the behavioral anomalies in patients with structural rearrangements of the sex chromosomes is not fully understood [Heinritz et al., 2005].
Arnedo et al.  reported a case of a transmitted SRY-positive ring Y chromosome from the father to his KS son. The frequency of ring chromosomes in clinically detected conceptions is 1:25,000 and has been reported for all human chromosomes [Arnedo et al., 2005]. In most of the cases a mosaic is presented and only ≤1% of all the ring chromosomes are inherited. In the study of Arnedo et al. , the boy had a 47,XX,r(Y)/46,XX karyotype and his father a 46,X,r(Y)/45,X karyotype. All men with a r(Y) studied so far were infertile and also the father showed a moderate oligozoospermia (4.5 × 106 sperm/ml) which could be explained by the arrest of the spermatocytes during meiosis [Arnedo et al., 2005]. However, his wife became pregnant by natural conception. Both the father and his son showed no phenotype abnormalities and their intelligence level was reported as normal. Because of the normal body height of the father the group suggested that the loss of genetic material implicated in ring Y formation may not have included the SHOX locus on Yp. Via microsatellite DNA markers the paternal origin of the additional X chromosome could also be detected. Further information like the hormonal status was not provided in the study.
In conclusion, most of the patients show some typical phenotype features of KS like small testes or increased FSH and LH levels. In one of the patients an increased aggressive and primitive behavior could be determined, whereas all other patients presented with normal behavior and intelligence levels despite from their aberration on the Y chromosome. A comparison of the cases is not possible because the rearrangements are located on diverse parts of the Y chromosome.
Men with a 46,XX Karyotype Including Patients with Ambiguous Genitalia
Sex reversal syndrome (SRS) is a human genetic disease, which is characterized by inconsistency between gonadal sexuality and chromosome sexuality and includes 46,XY females and 46,XX males [Wang et al., 2009]. The XX male SRS, also called de la Chapelle syndrome, was first characterized in 1972 [de la Chapelle, 1972]. With an incidence of 1:20,000–25,000 the syndrome is rare [Rajender et al., 2006]. Most XX men result from an abnormal X-Y interchange while spermatogenesis. During meiosis the human X and Y chromosomes pair in homologous regions named pseudoautosomal region 1 (PAR1) on Xp22. 3 and Yp11.3 and pseudoautosomal region 2 (PAR2) on Xq28 and Yq12. PAR1 spans about 2.7 Mb and PAR2 about 0.33 Mb on each chromosome. A translocation of Y material, which includes the key sex-determining region (SRY) that is located centromeric to PAR1, to the X chromosome during paternal meiosis results in 46,XX males, with normal male sexual development [Ferguson-Smith, 1966; Rigola et al., 2002].
Individuals with 46,XX maleness can be classified as Y-positive or Y-negative according to the presence or absence of the SRY gene [Valetto et al., 2005]. Approximately 90% of the patients without ambiguous genitalia carry Y-derived material, particularly the SRY gene caused by an X/Y or Y/autosome rearrangement [Ramos et al., 1996]. In agreement most XX males with ambiguous genitalia are SRY negative [Ramos et al., 1996]. In XX individuals 1 of the 2 X chromosomes is inactivated in early embryonic development as a mechanism of dosage compensation for sex-linked genes [Sharp et al. , 2005]. A skewed X inactivation was found in XX males with complete masculinization. Also, XX sex-reversed individuals with incomplete masculinization commonly show non-random inactivation, preferentially of the SRY-carrying X chromosome [Bouayed Abdelmoula et al., 2003]. Sharp et al.  suggested that incomplete masculinization in cases of X/Y translocations is a result of abnormal SRY gene expression by a positional effect, rather than X chromosome inactivation.
While the clinical symptoms of XX male patients often show some degree of heterogeneity [Ergun-Longmire et al., 2005], usually, the development of genitalia is normal and masculinity signs are obvious in SRY gene-positive patients [Wang et al., 2009]. Development of the genitals and sex psychology was described to be normal as well as erection and ejaculation, and there are almost no significant signs except cryptorchidism before puberty in most of the patients [Wang et al., 2009]. In most of the cases the patients are found by chromosome analysis for the reason of infertility. The clinical and laboratory data on XX male patients are summarized in table 4.
Clinical features in 149 patients with KS and a 46,XX karyotype sorted by the year of publication
Only 3 cases have been described in the literature about 46,XX men with SRY located on an autosomal chromosome [Dauwerse et al., 2006; Queralt et al., 2008; Chien et al., 2009]. It was postulated that the translocation between the SRY carrying Y chromosome and an autosomal chromosome was due to nonhomologous recombination between the autosomal chromosome and Ypter (containing SRY locus) during paternal meiosis [Queralt et al., 2008; Chien et al., 2009]. Regarding the phenotype there are no differences between the patients with the SRY gene on the X chromosome and the patients carrying the SRY gene on an autosomal chromosome.
On the contrary, SRY gene-negative patients can often be easily discriminated due to abnormality of genitalia shortly after birth. Some patients even show genital ambiguity [Ergun-Longmire et al., 2005] and belong to the group of true hermaphrodites and in some cases the patients have normal male genitalia in face of SRY-negative 46,XX karyotype [Rajender et al., 2006; Mustafa and Mehmet, 2010]. In many cases masculinity signs are not clear in SRY-negative patients. Mainly in adult patients, breast development and female secondary sex characteristics were found. Domenice et al.  proposed that 90% of 46,XX males carried Y chromosome material including the SRY gene. There have been postulated 2 different theories for the remaining 10%: The first indicates that a structural gene that determines human gender could be located on an autosomal chromosome which is regulated by X chromosome inactivation and the activation of Y chromosome [Wang et al., 2009]. Due to defects in the X inactivation, which result in spontaneous activation of a downstream gene in the absence of SRY, 46,XX males could develop [Wang et al. , 2009]. In previous studies, other genes in mouse and goat have been identified that lead, in the case of a mutation, to SRS. The corresponding homologs in human, FOXL2 (forkhead box L2) and WNT4 (wingless-type MMTV integration site family, member 4) were also mostly analyzed since these findings [Temel et al., 2007]. In different studies it was postulated that NR0B1 (nuclear receptor subfamily 0, group B, member 1), also known as DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1) acts as an anti-testis gene by antagonizing SRY function and that this genemay be necessary for testis development and its effect seems to be dosage sensitive [Ergun-Longmire et al., 2005]. Domenice et al.  analyzed mutations in the DAX1 and the WNT4 genes in sex-reversed patients and found out that the dosage of these genes was normal in their patients. With the help of these data, they proposed that the DAX1 and WNT4 are rarely involved in the etiology of male gonadal development in sex-reversed patients. This fact suggests the presence of other genes in the sex determination cascade.
The second hypothesis is about a SOX9 gene (SRY box-related gene 9) overexpression. It was suggested that this gene might function downstream to the SRY gene in the sex-determination pathway. Therefore, an upregulation of SOX9 expression caused by chromosomal abnormalities or mediated by other bypass activation mutations could lead to female-to-male sex reversal in 46,XX SRY-negative males [Dorsey et al., 2009; Wang et al., 2009].
Maciel-Guerra et al.  identified in 2008 a case of XX maleness and XX true hermaphroditism in SRY-negative monozygotic twins, suggesting that these entities might represent pleomorphic manifestations of the same disorder of gonadal development. Rajender et al.  also described an SRY-negative man with 46,XX karyotype who presented with normal genitalia. The group did not find a mutation in the coding region of the SOX9 and the DAX1 gene and no copy number variant in the SOX9 gene. In general, the reported patients with SRY-negative 46,XX karyotype have small or undescended testes [Valetto et al., 2005; Rajender et al., 2006; Temel et al., 2007; Dorsey et al., 2009] and in part additional ovarian tissue [Maciel-Guerra et al., 2008; Dorsey et al., 2009]. Most of the men have normal body hair and no gynecomastia. In that part they differ from the ‘normal’ KS patients. However, the hormone status shows the typically increased FSH and LH values and normal to decreased testosterone levels.
Women with a 47,XXY Karyotype
Searching in PubMed we found only 13 cases describing a female phenotype with a 47,XXY karyotype and one patient with a 47,XX+der(Y) karyotype. Seven of these cases have been diagnosed as suffering from androgen insensitivity (testicular feminization) syndrome resulting from mutations in the androgen receptor (AR) gene [German and Vesell, 1966; Bartsch-Sandhoff et al., 1976; Gerli et al., 1979; Müller et al., 1990; Uehara et al. , 1999; Saavedra-Castillo et al., 2005; Girardin et al., 2009]. Only 3 cases are reported about women with an additional or at least parts of the Y chromosome. One report describes a mother and her daughter with a 47,XXY SRY-negative karyotype [Röttger et al., 2000] and the other a woman with a 47,XX+mar karyotype where the extra chromosome contained centromeric DNA derived from the Y chromosome [Causio et al., 2002]. In the other two 47,XXY female cases, the cause for their femaleness could not be clarified [Schmid et al., 1992; Thangaraj et al., 1998]. The clinical and laboratory data of the reported 47,XXY women are summarized in table 5.
Clinical features in 13 female patients with KS and a 47,XXY karyotype sorted by the year of publication
The complete androgen insensitivity syndrome (CAIS) describes an X-linked disorder in which affected people have normal female external genitalia, female breast development, absence of the müllerian structures and abdominal or inguinal testes, despite a normal male karyotype. At puberty, female secondary sex characteristics like breasts develop, but menstruation and fertility do not. The prevalence of CAIS is estimated between 1 in 20,000–60,000 births [Girardin et al., 2009]. It is due to mutations in the AR gene, which is located on the X chromosome on Xq12 and may occur de novo or be inherited.
Normally, a defect resulting from a mutant AR allele on one X chromosome is masked by the effect of the normal allele on the other X chromosome [Uehara et al., 1999]. In 2009, two different hypotheses were suggested that could explain a CAIS phenotype in a 47,XXY individual. The first is that the homozygosity for the mutated AR gene implies either complete or partial maternal molecular identical material. The second hypothesis involves 2 different X chromosomes with 2 different AR alleles but with skewed X inactivation of the nonmutated X chromosome [Girardin et al., 2009].
The external genitalia like breast development or formation of the vagina differ in the reported cases. German and Vesell  described monozygotic female twins with a 47,XXY karyotype and normal female external genitalia. However, Saavedra-Castillo et al.  reported a woman with the same karyotype but hypoplasia of labial folds, clitoris, and vagina. Apart from that, the internal genitalia are nearly similar. All patients are characterized by the absence of the uterus and ovaries. Most of them have no wolffian and müllerian ducts but testes. Interestingly, in most of the described cases the testosterone levels were lower than expected in androgene insensitivity. This could be explained by testicular dysgenesis due to the 47,XXY karyotype. Just in one case the testosterone and LH levels were increased as expected in CAIS [Girardin et al., 2009]. The high FSH level likely reflects testicular dysgenesis in the context of the 47,XXY karyotype. Girardin et al.  found a point mutation in the AR gene on both X chromosomes and Uehara et al.  found 2 mutations in the AR gene in a 30-year-old woman with severely increased hormone levels. This can explain why CAIS occurred in this XXY patient. In the other cases the AR gene was not sequenced.
Röttger et al.  reported the only 2 cases of women with an SRY-negative 47,XXY karyotype. They described these 47,XXY females resulting from an aberrant X-Y interchange with transfer of Xp material onto Yp, with concomitant loss of the SRY gene. The 2 patients are mother and daughter, which is very uncommon because normally XXY women are sterile. The data of Röttger et al.  indicated that the Y chromosome in the mother and, by inference, in the daughter show a replacement of the Yp material that includes SRY and PRKY (protein kinase, Y-linked) by Xp material up to and including PRKX (protein kinase, X-linked). The absence of SRY explains the sex reversal in these two 47,XXY females. One X and the Y chromosome in the daughter were inherited from the mother. Her phenotype was not described. At her birth the daughter showed a female phenotype with normal external genitalia and bilateral clubbed feet. Two years later a patient was reported with a normal female karyotype but an additional marker chromosome, resembling an Y chromosome in size and QFQ-staining pattern [Causio et al., 2002]. The woman presented an apparently normal female habitus, with normal secondary sexual development. The extra chromosome contained centromeric regions of the Y. By means of sequence-tagged-sites PCR the absence of the SRY gene and the presence of the AZF genes could be defined. In none of 2 further reports the reason of the femaleness could be determined [Schmid et al., 1992; Thangaraj et al., 1998].
A comparison between the symptoms of a Klinefelter patient and a 47,XXY female is hardly possible because most of the KS symptoms also relate to a more feminine expression of certain body parts (e.g. gynecomastia). Symptoms like a tall stature, sparse body and pubic hair development, and elevated FSH and LH levels occur in most but not all of the described women. These characteristics are similar to those of KS.
Other Numeric Sex Chromosome Abnormalities
Besides the 47,XXY karyotype, a less frequent group of KS patients have additional X and/or Y chromosomes and show karyotypes like 48,XXYY, 48,XXXY, or 49,XXXXY [Visootsak and Graham, 2009].
48,XXYY syndrome occurs in approximately 1:17,000–1:45,000 males [Borja-Santos et al., 2010]. The physical features have been described to be similar to 47,XXY but with some more pronounced phenotypic abnormalities. These are mild craniofacial dysmorphism, skeletal anomalies such as radioulnar synostosis and clinodactyly, lower IQ (typically between 70 and 80), significant developmental delays, and medical problems like neurological symptoms such as intention tremor, poor dentition, or reactive airway disease [Lenroot et al., 2009; Visootsak and Graham, 2009]. The behavior of the patients is described to be shy and reserved. It can include hyperactivity, attention problems, impulsivity, aggression, mood instability, ‘autistic-like’ behaviors, and poor social function [Lenroot et al. , 2009; Visootsak and Graham, 2009]. In comparison to 47,XXY patients, men with 48,XXYY karyotype show a greater impairment in cognitive, verbal, and social functioning [Visootsak and Graham, 2009] and also the physical height is increased [Lenroot et al., 2009]. Tartaglia et al.  reported a cohort of 95 subjects ranging from 1 to 55 years of age and having a 48,XXYY karyotype. 92% of the men showed speech/language delays and 100% received special education for learning disabilities. The group found common medical problems including allergies and asthma, congenital heart defects, radioulnar synostosis, inguinal hernia and/or cryptorchidism, and seizures in the patients [Tartaglia et al., 2008]. In the adulthood, medical features like hypogonadism, deep vein thrombosis, intention tremor, and type II diabetes were found [Tartaglia et al., 2008, 2009]. In the same year, Zhang and Li  reported a case with 48,XXYY karyotype. They proposed the origin of this karyotype in a successive nondisjunction during paternal meiosis I and II. As the father of the patient was 56 years old, this case adds to the evidence that an age-related increase in sex chromosomal aneuploidies occurs in sperm.
The 48,XXXY karyotype is considered a variant of KS with features generally more pronounced than 47,XXY but less severe than 49,XXXXY and with an incidence of 1:17,000 to 1:50,000 in male births it is uncommon [Linden et al., 1995; Venkateshwari et al., 2010]. Affected males show a normal to tall stature with a decreased upper segment to lower segment ratio, hypertelorism and epicanthic folds, simplified ears and mild prognathism, skeletal anomalies including clinodactyly, abnormalities of the elbows and radioulnar synostosis, hypergonadotropic hypogonadism and testicular histology similar to 47,XXY and 48,XXYY, gynecomastia, and an abnormal glucose tolerance [Linden et al., 1995]. One fourth of these patients has a hypoplastic penis and is infertile [Linden et al., 1995]. In accordance with Zhang and Li , the IQs of the patients range between 40 and 60, and a greater deficit in daily living skills, communication, and socialization in comparison to 48,XXYY cases could be detected [Visootsak et al. , 2007]. Behavioral characteristics are immaturity, passivity, and irritability with temper tantrums [Visootsak and Graham, 2009]. Similarities to the 48,XXYY males are the activity level, the helpfulness, the pain tolerance, the morality, and the rejection based on the Reiss Personality Profile [Visootsak et al., 2007].
The rarest of the described variants in this review is the 49,XXXXY that shows an incidence of 1:85,000 to 1:100,000, and is in addition described to be the most severe variant of KS [Linden et al., 1995]. The extra X chromosomes in this variant accrue during maternal meiosis I and II and are the product of a double nondisjunction event [Simsek et al., 2009]. A correlation between maternal age and 49,XXXXY syndrome could not be detected in previous studies [Celik et al., 1997]. Clinical features of the syndrome are a coarse face with microcephaly, ocular hypertelorism, flat nasal bridge, upslanting palpebral fissures, bifid uvula and/or cleft palate, skeletal abnormalities including radioulnar synostosis, genu valgum, pes cavus, or clinodactyly, short stature with hypotonia, hyperextensible joints, and underdeveloped genitalia with hypergonadotropic hypogonadism [Visootsak et al. , 2007]. The behavior of affected people is described as timid and shy to friendly, but the patients show a low frustration tolerance and so irritability and bout of temper can occur sometimes [Linden et al., 1995]. The IQs of the patients range between 20 to 60 points [Linden et al., 1995]. Therefore, mental retardation was long described to be a characteristic feature for the syndrome. However, recent studies have reported that cognitive delays were not as significant as described in the past and personalities and learning styles are similar to 47,XXY cases [Samango-Sprouse, 2001; Visootsak et al., 2001, 2007; Visootsak and Graham, 2006; Gropman et al., 2010]. Variability in clinical and cognitive functioning may reflect skewed X inactivation, mosaicism, or other factors that warrant further investigation [Gropman et al., 2010]. Recently, Ottesen et al.  reported a study about the increased height in patients with additional sex chromosomes. In line with other reports [Bojesen and Gravholt, 2007; Tartaglia et al. , 2008], they found an increased stature in subjects with 47,XXY, 47,XYY, or 48,XXYY karyotypes. In patients with a 49,XXXXY karyotype the stature was reduced and for that the group suggests a nonlinear effect of the number of sex chromosomes on height [Ottesen et al., 2010]. Altogether, the phenotypic features of 49,XXXXY patients share some characteristics with 47,XXY, but there are also other unique and distinctive traits.
In conclusion, the effects on physical and mental development increase with the number of extra X chromosomes, and each X reduces the overall IQ by 15–16 points, with language most affected [Polani, 1969]. In addition, it was found that height decreases and radioulnar synostosis becomes more frequent as the number of X chromosomes increases [Visootsak et al., 2007].
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Dieter Kotzot, Division for Human Genetics
Department for Medical Genetics, Molecular and Clinical Pharmacology
Innsbruck Medical University, Schoepfstrasse 41
AT–6020 Innsbruck (Austria)
Tel. +43 512 9003 70531, E-Mail [email protected]
Article / Publication Details
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Published online: April 29, 2011
Issue release date: June 2011
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ISSN: 1661-5425 (Print)
eISSN: 1661-5433 (Online)
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Center for Molecular Genetics – Chromosomal abnormalities
This brochure contains information on what chromosomal abnormalities are, how they can be inherited, and what problems may be associated with them.This brochure cannot replace your communication with your doctor, but it can help you when discussing issues of interest to you.
In order to better understand what chromosomal abnormalities are, it will be helpful first to know what genes and chromosomes are.
What are genes and chromosomes?
Our body is made up of millions of cells. Most cells contain a complete set of genes. Man has thousands of genes. Genes can be compared to instructions used to control growth and coherence throughout the body.Genes are responsible for many of the traits in our bodies, such as eye color, blood type, or height.
Genes are located on threadlike structures called chromosomes. Normally, most cells in the body contain 46 chromosomes. Chromosomes are passed on to us from our parents – 23 from mom, and 23 from dad, so we often look like our parents. Thus, we have two sets of 23 chromosomes, or 23 pairs of chromosomes. Since genes are located on chromosomes, we inherit two copies of each gene, one copy from each of the parents.Chromosomes (and hence genes) are made up of a chemical compound called DNA.
Figure 1: Genes, Chromosomes and DNA
Chromosomes (see Figure 2), numbered 1 through 22, are the same in males and females. These chromosomes are called autosomes. The chromosomes of the 23rd pair are different in women and men, and they are called sex chromosomes. There are 2 variants of sex chromosomes: the X chromosome and the Y chromosome. Normally, women have two X chromosomes (XX), one of them is transmitted from the mother, the other from the father.Men normally have one X chromosome and one Y chromosome (XY), with the X chromosome passed from the mother and the Y chromosome from the father. So, in Figure 2, the chromosomes of a man are shown, since the last, 23rd, pair is represented by a combination of XY.
Figure 2: 23 pairs of chromosomes distributed by size; chromosome number 1 is the largest. The last two chromosomes are sex chromosomes.
The correct chromosome set is very important for the normal development of a person.This is due to the fact that the genes that give “instructions for action” to the cells of our body are located on the chromosomes. Any change in the number, size, or structure of our chromosomes could mean a change in the amount or sequence of genetic information. Such changes can lead to learning difficulties, developmental delays and other health problems for the child.
Chromosomal changes can be inherited from parents. Most often, chromosomal changes occur at the stage of the formation of an egg or sperm, or during fertilization (newly arisen mutations, or de novo mutations).These changes cannot be controlled.
There are two main types of chromosomal changes. Change in the number of chromosomes. With such a change, there is an increase or decrease in the number of copies of any chromosome. Changes in the structure of chromosomes. With such a change, the material of any chromosome is damaged, or the sequence of genes is changed. The appearance of additional or loss of part of the original chromosomal material is possible.
In this brochure we will look at chromosomal deletions, duplications, insertions, inversions, and ring chromosomes.If you are interested in information on chromosomal translocations, please refer to the brochure “Chromosomal Translocations”.
Change in the number of chromosomes.
Normally, each human cell contains 46 chromosomes. However, sometimes a baby is born with either more or fewer chromosomes. In this case, there appears, respectively, either an excess or an insufficient number of genes necessary to regulate the growth and development of the organism.
One of the most common examples of a genetic disorder caused by an excess of chromosomes is Down syndrome.In the cells of people with this disease, there are 47 chromosomes instead of the usual 46, since there are three copies of the 21st chromosome instead of two. Other examples of diseases caused by an excess of chromosomes are Edwards and Patau syndromes.
Figure 3: Chromosomes of a girl (last pair of chromosomes XX) with Down syndrome. Three copies of chromosome 21 are visible instead of two.
Changes in the structure of chromosomes.
Changes in the structure of chromosomes occur when the material of a particular chromosome is damaged, or the sequence of genes is changed.Structural changes also include excess or loss of some chromosomal material. This can happen in several ways, described below.
Changes in the structure of chromosomes can be very small, and it can be difficult for specialists in laboratories to detect them. However, even if a structural change is found, it is often difficult to predict the impact of this change on the health of a particular child. This can be frustrating for parents who want comprehensive information about their child’s future.
If you would like to learn more about translocations, please refer to the brochure Chromosomal Translocations.
The term “chromosomal deletion” means that part of a chromosome has been lost or shortened. Deletions can occur on any chromosome and along any part of the chromosome. The deletion can be of any size. If the material (genes) lost during the deletion contained important information for the body, then the child may experience learning difficulties, developmental delay and other health problems.The severity of these manifestations depends on the size of the lost part and localization within the chromosome. An example of such a disease is Joubert’s syndrome.
The term “chromosomal duplication” means that part of a chromosome has been duplicated, and because of this, there is an excess of genetic information. This excess chromosome material means the body is receiving too many “instructions” and this can lead to learning difficulties, developmental delays and other health problems for the child.An example of a disease caused by the duplication of a portion of chromosomal material is motor-sensory neuropathy type IA.
Chromosomal insertion (insertion) means that part of the chromosome material was “out of place” on the same or on another chromosome. If the total amount of chromosomal material has not changed, then such a person is usually healthy. However, if such a movement leads to a change in the amount of chromosomal material, then the person may have learning difficulties, developmental delay and other health problems of the child.
The term “ring chromosome” means that the ends of the chromosome are connected, and the chromosome has acquired the form of a ring (in the normal human chromosomes have a linear structure). This usually happens when both ends of the same chromosome are shortened. The remaining ends of the chromosome become “sticky” and join together to form a “ring”. The consequences of the formation of ring chromosomes for the body depend on the size of the deletions at the ends of the chromosome.
Chromosomal inversion means such a change in the chromosome in which part of the chromosome is unfolded, and the genes in this region are arranged in reverse order.In most cases, the inversion carrier is healthy.
If a parent has an unusual chromosomal rearrangement, how might this affect the child?
Several outcomes of each pregnancy are possible:
- A child can receive a perfectly normal set of chromosomes.
- A child may inherit the same chromosomal rearrangement that a parent has.
- The child may have learning difficulties, developmental delay, or other health problems.
- Possible spontaneous abortion.
Thus, healthy children can be born to a carrier of a chromosomal rearrangement, and in many cases this is exactly what happens. Since each adjustment is unique, your specific situation should be discussed with your geneticist. It often happens that a child is born with a chromosomal rearrangement, despite the fact that the chromosome set of the parents is normal. Such restructuring is called newly emerging, or emerging “de novo” (from the Latin word).In these cases, the risk of re-birth of a child with a chromosomal rearrangement in the same parents is very small.
Diagnostics of chromosomal rearrangements
It is possible to carry out genetic analysis to detect the carriage of chromosomal rearrangements. For analysis, a blood sample is taken, and the blood cells are examined in a specialized laboratory to detect chromosomal rearrangements. This analysis is called karyotyping. It is also possible to perform a test during pregnancy to assess the chromosomes of the fetus.This test is called prenatal diagnosis and should be discussed with your geneticist. For more information, see the brochures Chorionic villus sampling and Amniocentesis.
As for other family members
If a family member has a chromosomal rearrangement, you may want to discuss this with other family members. This will enable other relatives, if desired, to undergo an examination (analysis of chromosomes in blood cells) to determine the carriage of chromosomal rearrangements.This can be especially important for relatives who already have children or are planning a pregnancy. If they are not carriers of a chromosomal rearrangement, they cannot pass it on to their children. If they are carriers, then they may be asked to undergo an examination during pregnancy to analyze the chromosomes of the fetus.
Some people find it difficult to discuss chromosomal rearrangement problems with family members. They may be afraid to disturb family members. In some families, because of this, people experience difficulties in communication and lose understanding with relatives.Geneticists are usually experienced in dealing with such family situations and can help you discuss the problem with other family members.
Points to Remember
- Chromosomal rearrangements can either be inherited from parents or occur during fertilization.
- Perestroika cannot be corrected – it remains for life.
- Rearrangement is not contagious, for example, its carrier may be a blood donor.
- People often feel guilty about having a problem in their family, such as a chromosomal rearrangement.It is important to remember that this is not someone else’s fault or the result of someone else’s actions.
- Most carriers of balanced rearrangements can have healthy children.
90,000 Scientists measured the mass of human chromosomes for the first time
British physicists using X-ray scanning have shown that the mass of the human chromosome is several times larger than expected – which may indicate its components unknown to science.
Researchers from University College London at the Diamond Light Source synchrotron in Oxford were able to measure the weight of all 46 human chromosomes – the elements of a cell that contain instructions for every cell in the body. X-rays of them showed that they are 20 times heavier than the DNA they contain. This suggests that it is possible that chromosomes contain a number of components still unknown to science – in addition to DNA and proteins, which, among other things, provide reading and “packing” of amino acids.
The scientists shared the results of their research in the journal Genome Research .
“Our measurements suggest that the 46 chromosomes in each of our cells weigh 242 picograms (one trillionth of a gram – Gazeta.Ru). This is more than we expected, and if the results are (independently experimentally – Gazeta.Ru) confirmed, it may indicate an unexplained excess mass of chromosomes, “- said lead author of the study, professor at the London Center for Nanotechnology, University College London, Ian Robinson.
In order to carry out such measurements, the researchers used the method of X-ray ptychography. In it, the sample is gradually irradiated with a bright X-ray beam. Researchers receive a set of diffractograms on the detector – pictures of the distribution of radiation, allowing them to obtain a spatial portrait of the area – from partially overlapping points of the object under study. The resulting diffraction patterns are then aligned. As a result, a 3D picture of the object is obtained.
Chromosomes of B- and T-lymphocytes (cells of the immune system) were irradiated at room temperature in metaphase – just before they split into chromatids, daughter cells.”Since DNA contains only atoms of light elements containing the same number of protons, neutrons and electrons, the number of electrons measured using ptychography will be exactly half the number of atomic mass units,” the scientists note in their article.
Ptychography helped researchers determine the electron density – the number of electrons – on a single chromosome. The rest mass of an electron is one of the fundamental physical constants, so scientists were able to easily calculate the desired chromosome mass.
Scientists have succeeded in constructing “X-ray” karyotypes – complete chromosome sets – both for cells labeled with heavy metals for better visualization, and for “normal” ones. The average mass of the first chromosome was 10.9 picograms with the expected 1.74. The sevenfold difference, scientists say, may indicate unaccounted for protein components of the chromosome.
This is far from the first ptychography X-ray study to study chromosomes – the first preliminary data on their mass were obtained by the same group of researchers in 2015.No less often, the method is used to obtain non-invasive images of both cells and even their nuclei. The method is also used in medical research – for example, with its help a group of German scientists measured the calcium content in human bones. Earlier, ptychography found its place in materials science: it was used to study both cement and silk.
90,000 Genetics of humans and apes. Why did man descend from ape
Scientific editor ANTHROPOGENES.RU, Ph.D., Associate Professor, Department of Anthropology, Faculty of Biology, Moscow State University Lomonosov
The reaching link
Specially for the portal “Anthropogenesis.RU”.
Author’s project of S. Drobyshevsky. The e-book will give readers basic information about what modern science knows about ancient human ancestry.
The relationship between humans and other primates is confirmed by the entire body of knowledge about primates. In terms of the overwhelming majority of parameters, humans are closest to chimpanzees and gorillas, and, apparently, are somewhat more related to chimpanzees than to gorillas, and of the two species of chimpanzees, the pygmy, the bonobos, seems to be more similar to humans.
Comparison of human and chimpanzee chromosomes.
It can be seen that the 2nd human chromosome corresponds to the 2nd chromosomes of chimpanzees.
Source: Jorge Yunis, DIAGRAM OF HUMAN AND CHIMP CHROMOSOME, Science 208: 1145-58 (1980). Courtesy of Science magazine.
General complexes of signs can be divided into groups for convenience:
– genetic data;
– Molecular Biological Data;
– anatomical data;
– embryological data;
– Behavior data.
According to genetic distances, all primates are arranged in a harmonious order, completely repeating the system built according to anatomical data. Of all the primates, chimpanzees are closest to humans, according to the most modern estimates, the common genome with which humans have about 94%, and sometimes even numbers up to 98% are called. Remarkably, the genetic differences between human men and women are greater than than, say, male and male chimpanzees. In addition, different groups of people or even specific individuals can have noticeable differences from each other, approaching in scale to the level of differences between chimpanzees and humans.However, chimpanzees have one more chromosome than humans: in human ancestors, two chromosomes merged together (this is clearly seen in the figure: the 2nd human chromosome is similar to the 2nd chromosomes of chimpanzees). From such a combination, the gene set of chromosomes did not change in any way, the information remained fundamentally the same.
90,000 It turned out that reproduction is possible without the male sex chromosome
Many learned in school biology lessons that information about the sex of a mammal is encrypted in two chromosomes: X and Y.These are paired structures inherited from father and mother. Females have two chromosomes X (XX), males have X and Y (XY).
One exception to this boring genetic rule has been known since the 1960s. Scientists did not pay much attention to it, because at that time it was not technically possible to find at least some explanation for this scientific phenomenon.
Modern genetics opens up opportunities for detailed DNA sequencing, which was used by researchers from California State University at San Francisco.
We are talking about the sex chromosomes of one small and, at first glance, nondescript rodent: the Oregon vole. In the distant past, the X and Y chromosomes of these babies merged in a strange way, leaving the sex cells of males with two X chromosomes, and females with one X chromosome in general. At the same time, Oregon voles continue to quietly produce males.
A more detailed study of this unusual DNA showed that the X chromosomes of both sexes contain genes, as it were, of the Y chromosome absorbed by them.None of the genetically closely related species of voles had such a feature, which suggests that the Oregon voles “abandoned” the full Y-chromosome a couple of million years ago.
Why don’t the females of these voles develop male sexual characteristics, if their sex chromosomes contain regions of “male” genes? Scientists suggest that in both females and males of this species of North American rodents, genetic mechanisms are turned on, forcing the corresponding genes to “silence”.
Answers to many questions related to this unusual type of inheritance still remain a mystery to scientists. Now the authors of the work can only assume that the reason for such genetic cutting may be the tendency of genes of voles of the genus Microtus to frequent changes.
Their chromosomes are rapidly evolving, and genes are easily “cut” and “glued” in sometimes unexpected places. It is possible that other species of these rodents undergo similar genetic changes, just much more slowly.
The study was published in the prestigious scientific journal Science.
Earlier we wrote that the Y chromosome determines not only the sex of the animal, but the female chromosome is actually responsible for the production of sperm.
More news from the world of science can be found in the “Science” section of the “Watch” media platform.
90,000 46 is the norm? We count chromosomes: how much does a person need to be happy
Let’s first agree on the terminology.Finally, human chromosomes were counted a little more than half a century ago – in 1956. Since then, we know that in somatic , that is, not germ cells, there are usually 46 of them – 23 pairs.
Chromosomes in a pair (one received from the father, the other from the mother) are called homologous to . They contain genes that perform the same functions, but often differ in structure. The exception is the sex chromosomes – X and Y, the gene composition of which does not completely coincide.All other chromosomes except sex chromosomes are called autosomes .
The number of sets of homologous chromosomes – ploidy – in germ cells is equal to one, and in somatic cells, as a rule, two.
Interestingly, not all mammalian species have a constant number of chromosomes. For example, in some representatives of rodents, dogs and deer, the so-called B-chromosome was found. These are small additional chromosomes, in which there are practically no regions encoding proteins, but they are divided and inherited along with the main set and, as a rule, do not affect the functioning of the body.It is believed that B chromosomes are simply duplicated pieces of DNA “parasitizing” on the main genome.
B-chromosomes have not yet been found in humans. But sometimes an additional set of chromosomes appears in the cells – then they talk about polyploidy , and if their number is not a multiple of 23 – about aneuploidy. Polyploidy occurs in certain types of cells and contributes to their enhanced work, while aneuploidy usually indicates a malfunction of the cell and often leads to its death.
Sharing must be honest
Most often, the wrong number of chromosomes is the result of unsuccessful cell division. In somatic cells, after DNA duplication, the maternal chromosome and its copy are linked together by cohesin proteins. Then, protein complexes of the kinetochora land on their central parts, to which microtubules are later attached. When dividing along microtubules, kinetochores disperse to different poles of the cell and pull chromosomes with them. If the cross-links between the copies of the chromosome are destroyed ahead of time, then microtubules from the same pole can attach to them, and then one of the daughter cells will receive an extra chromosome, and the second will remain deprived.
Division during the formation of germ cells (meiosis) is more complicated. After DNA duplication, each chromosome and its copy, as usual, are stitched together with cohesins. Then the homologous chromosomes (obtained from the father and mother), or rather their pairs, also link to each other, and the so-called tetrad , or four, is obtained. And then the cell will have to share two times. During the first division, homologous chromosomes diverge, that is, daughter cells contain pairs of identical chromosomes.And in the second division, these pairs diverge, and as a result, the sex cells carry a single set of chromosomes.
Meiosis also often fails with errors. The problem is that a construct of linked two pairs of homologous chromosomes can twist in space or separate in the wrong places. The result will again be an uneven distribution of chromosomes. Sometimes the germ cell manages to track this so as not to transmit the defect by inheritance. Extra chromosomes are often misplaced or torn apart, triggering a death program.For example, among spermatozoa, such a selection for quality operates. But the eggs were less fortunate. All of them are formed in humans even before birth, prepare for division, and then freeze. Chromosomes have already been doubled, tetrads are formed, and division is delayed. They live in this form until the reproductive period. Then the eggs ripen in turn, divide for the first time and freeze again. The second division occurs immediately after fertilization. And at this stage, it is already difficult to control the quality of the division. And the risks are greater, because the four chromosomes in the egg remain stitched for decades.During this time, breakdowns accumulate in the cohesins, and chromosomes can spontaneously separate. Therefore, the older a woman is, the more likely it is for an incorrect chromosome discrepancy in the egg.
Aneuploidy in the germ cells inevitably leads to aneuploidy of the embryo. When a healthy egg with 23 chromosomes is fertilized by a sperm with extra or missing chromosomes (or vice versa), the number of chromosomes in a zygote will obviously be different from 46. But even if the germ cells are healthy, this does not guarantee healthy development.In the first days after fertilization, the cells of the embryo are actively dividing in order to quickly gain cell mass. Apparently, during fast divisions there is no time to check the correctness of chromosome divergence, so aneuploid cells can arise. And if an error occurs, then the further fate of the embryo depends on the division in which it happened. If the balance is disturbed already in the first division of the zygote, then the whole organism will grow aneuploid. If the problem arose later, then the outcome is determined by the ratio of healthy and abnormal cells.
Some of the latter may die further, and we will never know about their existence. Or it can take part in the development of the organism, and then it will turn out to be mosaic – different cells will carry different genetic material. Mosaicism causes a lot of trouble for prenatal diagnosticians. For example, when there is a risk of giving birth to a child with Down syndrome, sometimes one or more cells of the embryo are removed (at a stage when this should not pose a danger) and the chromosomes in them are counted.But if the embryo is mosaic, then this method becomes not particularly effective.
All cases of aneuploidy are logically divided into two groups: lack and excess of chromosomes. The problems that arise with a deficiency are quite expected: minus one chromosome means minus hundreds of genes.
Arrangement of chromosomes in the nucleus of a human cell (chromosomal territories). Image: Bolzer et al., 2005 / Wikimedia Commons / CC BY 2.5
If the homologous chromosome is working normally, then the cell can get off only with an insufficient amount of proteins encoded there.But if some of the genes remaining on the homologous chromosome do not work, then the corresponding proteins in the cell will not appear at all.
In the case of an excess of chromosomes, things are not so obvious. There are more genes, but here – alas – more does not mean better.
First, the extra genetic material increases the load on the nucleus: an additional DNA strand needs to be placed in the nucleus and served by information reading systems.
Scientists have found that in people with Down syndrome, whose cells carry an additional 21st chromosome, the work of genes located on other chromosomes is mainly disrupted.Apparently, an excess of DNA in the nucleus leads to the fact that there are not enough proteins that support the work of chromosomes for everyone.
Secondly, the balance in the amount of cellular proteins is disturbed. For example, if activator proteins and inhibitor proteins are responsible for some process in the cell, and their ratio usually depends on external signals, then an additional dose of one or the other will lead to the fact that the cell will no longer adequately respond to an external signal. Finally, the aneuploid cell is more likely to die.When DNA is duplicated before division, errors inevitably occur, and the cellular proteins of the repair system recognize them, repair them and start doubling again. If there are too many chromosomes, then there are not enough proteins, errors accumulate and apoptosis is triggered – programmed cell death. But even if the cell does not die and divides, then the result of such division is also likely to be aneuploids.
You will live
If even within one cell aneuploidy is fraught with malfunction and death, it is not surprising that it is not easy for a whole aneuploid organism to survive.At the moment, only three autosomes are known – 13, 18 and 21, for which trisomy (that is, an extra, third chromosome in cells) is somehow compatible with life. This is probably due to the fact that they are the smallest and carry the least genes. At the same time, children with trisomy on the 13th (Patau syndrome) and 18th (Edwards syndrome) chromosomes live up to 10 years at best, and more often live less than a year. And only trisomy on the smallest in the genome, chromosome 21, known as Down syndrome, allows you to live up to 60 years.
People with general polyploidy are very rare. Normally, polyploid cells (carrying not two, but from four to 128 sets of chromosomes) can be found in the human body, for example, in the liver or red bone marrow. These are usually large cells with enhanced protein synthesis that do not require active division.
An additional set of chromosomes complicates the task of their distribution among daughter cells, so polyploid embryos, as a rule, do not survive. Nevertheless, about 10 cases have been described when children with 92 chromosomes (tetraploids) were born and lived from several hours to several years.However, as in the case of other chromosomal abnormalities, they lagged behind in development, including mental development. However, many people with genetic abnormalities come to the rescue of mosaicism. If the anomaly has already developed during the cleavage of the embryo, then some of the cells may remain healthy. In such cases, the severity of symptoms decreases and life expectancy increases.
However, there are also such chromosomes, the increase in the number of which is compatible with human life or even goes unnoticed.And this, surprisingly, is the sex chromosomes. The reason for this is gender inequity: about half of the people in our population (girls) have twice as many X chromosomes as others (boys). At the same time, X chromosomes not only serve to determine sex, but also carry more than 800 genes (that is, twice as many as the extra 21st chromosome, which causes a lot of trouble for the body). But girls are helped by a natural mechanism for eliminating inequality: one of the X chromosomes is inactivated, twisted and turns into a Barr’s body.In most cases, the choice is random, and in a number of cells, the maternal X chromosome is active as a result, and in others, the paternal one. Thus, all girls turn out to be mosaic, because different copies of genes work in different cells. Tortoiseshell cats are a classic example of this mosaic pattern: on their X chromosome there is a gene responsible for melanin (a pigment that determines, among other things, the color of the coat). Different copies work in different cells, so the color turns out to be spotty and is not inherited, since inactivation occurs randomly.
Tortoiseshell cat. Photo: Lisa Ann Yount / Flickr / Public domain
As a result of inactivation in human cells, only one X chromosome always works. This mechanism avoids serious troubles with X-trisomy (girls XXX) and Shereshevsky-Turner syndromes (girls XO) or Klinefelter (boys XXY). About one in 400 children is born this way, but vital functions in these cases are usually not significantly impaired, and even infertility does not always occur.It is more difficult for those who have more than three chromosomes. This usually means that the chromosomes did not separate twice during the formation of germ cells. Cases of tetrasomy (XXXX, XXYY, XXXY, XYYY) and pentasomy (XXXXX, XXXXY, XXXYY, XXYYY, XYYYY) are rare, some of them have been described only a few times in the history of medicine. All of these options are compatible with life, and people often live to old age, with abnormalities manifested in abnormal skeletal development, genital defects, and a decrease in mental capacity.Tellingly, the additional Y chromosome itself does not significantly affect the functioning of the body. Many men with the XYY genotype do not even know about their identity. This is due to the fact that the Y chromosome is much smaller than the X and carries almost no genes that affect the viability.
The sex chromosomes have another interesting feature. Many mutations in genes located on autosomes lead to abnormalities in the functioning of many tissues and organs. At the same time, most of the gene mutations on the sex chromosomes are manifested only in the violation of mental activity.It turns out that sex chromosomes control the development of the brain to a significant extent. Based on this, some scientists hypothesize that it is they who are responsible for the differences (however, not fully confirmed) between the mental abilities of men and women.
Who benefits from being wrong
Despite the fact that medicine has been familiar with chromosomal abnormalities for a long time, recently aneuploidy continues to attract the attention of scientists. It turned out that more than 80% of tumor cells contain an unusual number of chromosomes.On the one hand, the reason for this may be the fact that proteins that control the quality of division are capable of inhibiting it. In tumor cells, these very control proteins are often mutated, so the restrictions on division are removed and the chromosome check does not work. On the other hand, scientists believe that this can serve as a factor in the selection of tumors for survival. According to this model, tumor cells first become polyploid, and then, as a result of division errors, they lose different chromosomes or their parts.It turns out a whole population of cells with a wide variety of chromosomal abnormalities. Most of them are not viable, but some may accidentally be successful, for example, if they accidentally get additional copies of genes that trigger division, or lose genes that suppress it. However, if we further stimulate the accumulation of errors during division, then the cells will not survive. Taxol, a common cancer drug, is based on this principle: it causes systemic nondisjunction of chromosomes in tumor cells, which should trigger their programmed death.
It turns out that each of us can be a carrier of extra chromosomes, at least in individual cells. However, modern science continues to develop strategies to deal with these unwanted passengers. One of them proposes to use proteins responsible for the X chromosome, and set, for example, on the extra 21st chromosome of people with Down syndrome. It is reported that this mechanism has been activated in cell cultures. So, perhaps in the foreseeable future, dangerous extra chromosomes will be tamed and rendered harmless.
90,000 Mutations on human chromosome 16 lower IQ levels
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Scientists have discovered a gene, a mutation in which lowers IQ by 25 points. Reduced intelligence of a person in some cases can be caused by a mutation of chromosome 16 in DNA.
The dependence of intelligence on chromosome 16 was established by Swiss genetics. A group of scientists from the University of Lausanne (Switzerland) are conducting experiments, in particular, to determine the genes that are responsible for autism, schizophrenia and other mental illnesses.
More recently, scientists have discovered that an unusual mutation on chromosome 16, known as a “16p11.2 duplication”, leads to a range of syndromes associated with impaired consciousness – common among autistic and schizophrenic people, and also makes a person more susceptible to malnutrition and anorexia …
Scientists were interested in the effect on intelligence of “duplication 16p11.2” (the presence of two copies) – mutations in chromosome 16. To establish the dependence on its presence of human mental abilities, geneticists conducted a series of experiments with the participation of volunteers, about two hundred of which possessed either one or two extra copies of 16p11.2, and asked them to take a series of tests to determine IQ and the degree of development of autism.
As this experiment showed, the presence of two copies of 16p11.2 was associated with serious impairments in intellectual development – carriers of such mutations, on average, had IQs 25 points lower than people without such mutations, and 16 points lower than their relatives who possessed only one such extra copy. Deleting one of the normal 16p11 copies had similar consequences.2, causing a similar drop in IQ.
In addition to a decrease in intelligence, the appearance of additional copies of 16p11.2 was associated with an increased susceptibility to epilepsy and the development of various disorders and deformations in the structure of the brain and blood vessels of the head. In addition, carriers of these mutations later began to walk and, in general, suffered from mental disorders more often.
Such a sharp drop in IQ actually transfers the owners of this mutation from the category of normal people, whose IQ is approximately equal to 100-105 points, to the category of mentally retarded individuals, whose IQ often approached the 65-70 points mark.Further study of 16p11.2, the authors of the article hope, will help to understand whether it is possible to combat such disorders and how doctors can help children with such genetic defects to keep up with development.
Research published in JAMA Psychiatry
90,000 Pregnancy: diagnosis of chromosomal abnormalities
A chromosomal abnormality is any change in the number or structure of chromosomes. The most famous of these is trisomy on the 21st pair of chromosomes (Down syndrome or Mongolism).In addition, there are many other anomalies. Some of them are incompatible with life and, as a rule, cause miscarriages, others lead to impaired psychomotor development of varying severity, and some changes do not have any adverse manifestations and do not affect a person’s life.
The only way to know if your baby has a similar abnormality is to perform tests such as amniocentesis or trophoblast biopsy, which will help determine the karyotype of the fetus.A karyotype is a genetic map of a child. But such studies are carried out only in cases where the risk of a child having a chromosomal abnormality is significantly increased. Therefore, it is very important to accurately assess the likelihood of a chromosomal abnormality.
There are many ways to calculate this risk. They are all well studied from a scientific point of view, but the best method is one that requires a minimum number of tests (and, therefore, allows you to reduce the frequency of unjustified miscarriages), and at the same time allows you to determine the risk of possible chromosomal abnormalities as accurately as possible.
Taking into account these requirements, scientists recommend using a method of determining the degree of risk, which takes into account the following three indicators:
The degree of risk associated with the age of the expectant mother: it is known that the risk of a chromosomal abnormality increases with the age of a woman. For example, the probability of a chromosomal abnormality in the mother’s fetus at the age of 20 is 1/1500, and by the age of 39 it rises to 1/128;
The degree of risk associated with the thickness of the occipital fold of the fetus.This indicator is determined by a gynecologist during an ultrasound scan in the period from 11 to 13 weeks for amenorrhea;
The degree of risk, determined by the level of certain substances in the mother’s blood during the first trimester of pregnancy (beta-hCG and PAPP-A protein).
These three metrics can be used to calculate the overall risk of having a chromosomal abnormality.