X chromosome

From Wikipedia, the free encyclopedia

 

Human X chromosome
Human X chromosome (after G-banding)
X chromosome in human male karyogram
Features
Length (bp)	156,040,895 bp (GRCh38)
No. of genes	804 (CCDS)
Type	Allosome
Centromere position	Submetacentric (61.0 Mbp)
Complete gene lists
CCDS	Gene list
HGNC	Gene list
UniProt	Gene list
NCBI	Gene list
External map viewers
Ensembl	Chromosome X
Entrez	Chromosome X
NCBI	Chromosome X
UCSC	Chromosome X
Full DNA sequences
RefSeq	NC_000023 (FASTA)
GenBank	CM000685 (FASTA)

The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, following its subsequent discovery.

Discovery

It was first noted that the X chromosome was special in 1890 by Hermann Henking in Leipzig. Henking was studying the testicles of Pyrrhocoris and noticed that one chromosome did not take part in meiosis. Chromosomes are so named because of their ability to take up staining (chroma in Greek means color). Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of object and consequently named it X element, which later became X chromosome after it was established that it was indeed a chromosome.

The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.

It was first suggested that the X chromosome was involved in sex determination by Clarence Erwin McClung in 1901. After comparing his work on locusts with Henking's and others, McClung noted that only half the sperm received an X chromosome. He called this chromosome an accessory chromosome, and insisted (correctly) that it was a proper chromosome, and theorized (incorrectly) that it was the male-determining chromosome.

Inheritance pattern

The number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence. (After Hutchison, L. "Growing the Family Tree: The Power of DNA in Reconstructing Family Relationships".)

 

Luke Hutchison noticed that a number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence. A male individual has an X chromosome, which he received from his mother, and a Y chromosome, which he received from his father. The male counts as the "origin" of his own X chromosome (${\displaystyle F_{1}=1}$), and at his parents' generation, his X chromosome came from a single parent (${\displaystyle F_{2}=1}$). The male's mother received one X chromosome from her mother (the son's maternal grandmother), and one from her father (the son's maternal grandfather), so two grandparents contributed to the male descendant's X chromosome (${\displaystyle F_{3}=2}$). The maternal grandfather received his X chromosome from his mother, and the maternal grandmother received X chromosomes from both of her parents, so three great-grandparents contributed to the male descendant's X chromosome (${\displaystyle F_{4}=3}$). Five great-great-grandparents contributed to the male descendant's X chromosome (${\displaystyle F_{5}=5}$), etc. (Note that this assumes that all ancestors of a given descendant are independent, but if any genealogy is traced far enough back in time, ancestors begin to appear on multiple lines of the genealogy, until eventually, a population founder appears on all lines of the genealogy.)

Humans

Function

Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH. Shown is a single optical section made with a confocal microscope. Bottom: Same nucleus stained with DAPI and recorded with a CCD camera. The Barr body is indicated by the arrow, it identifies the inactive X (Xi).

 

The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 800 protein-coding genes compared to the Y chromosome containing about 70 genes, out of 20,000–25,000 total genes in the human genome. Each person usually has one pair of sex chromosomes in each cell. Females have two X chromosomes, whereas males have one X and one Y chromosome. Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother. This inheritance pattern follows the Fibonacci numbers at a given ancestral depth. 

Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked. If X chromosome has a genetic disease gene, it always causes illness in male patients, since men have only one X chromosome and therefore only one copy of each gene. Females, instead, may stay healthy and only be carrier of genetic illness, since they have another X chromosome and possibility to have healthy gene copy. For example hemophilia and red-green colorblindness run in family this way. 

The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex determination. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in nearly all somatic cells (cells other than egg and sperm cells). This phenomenon is called X-inactivation or Lyonization, and creates a Barr body. If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the Barr body may be more biologically active than was previously supposed.

The partial inactivation of the X-chromosome is due to repressive heterochromatin that compacts the DNA and prevents the expression of most genes. Heterochromatin compaction is regulated by Polycomb Repressive Complex 2 (PRC2).

Genes

Number of genes

The following are some of the gene count estimates of human X chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.

Estimated by	Protein-coding genes	Non-coding RNA genes	Pseudogenes
CCDS	804	—	—
HGNC	825	260	606
Ensembl	841	639	871
UniProt	839	—	—
NCBI	874	494	879

Gene list

The following is a partial list of genes on human chromosome X.

• APOO: encoding protein Apolipoprotein O
• ARMCX6: encoding protein Armadillo repeat containing X-linked 6
• BEX1: encoding protein Brain-expressed X-linked protein 1
• BEX2: encoding protein Brain-expressed X-linked protein 2
• BEX4: encoding protein Brain expressed, X-linked 4
• CCDC120: encoding protein Coiled coil domain containing protein 120
• CCDC22: encoding protein Coiled-coil domain containing 22
• CD99L2: CD99 antigen-like protein 2
• CHRDL1: encoding protein Chordin-like 1
• CMTX2 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 2 (recessive)
• CMTX3 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 3 (dominant)
• CT45A5: encoding protein Cancer/testis antigen family 45, member A5
• CXorf36: encoding protein hypothetical protein LOC79742
• CXorf40A: Chromosome X open reading frame 40
• CXorf49: chromosome X open reading frame 49. encoding protein
• CXorf66: encoding protein Chromosome X Open Reading Frame 66
• CXorf67: encoding protein Uncharacterized protein CXorf67
• DACH2: encoding protein Dachshund homolog 2
• EFHC2: encoding protein EF-hand domain (C-terminal) containing 2
• ERCC6L encoding protein ERCC excision repair 6 like, spindle assembly checkpoint helicase
• F8A1: Factor VIII intron 22 protein
• FAM120C: encoding protein Family with sequence similarity 120C
• FAM122B: Family with sequence similarity 122 member B
• FAM122C: encoding protein Family with sequence similarity 122C
• FAM127A: CAAX box protein 1
• FAM50A: Family with sequence similarity 50 member A
• FATE1: Fetal and adult testis-expressed transcript protein
• FMR1-AS1: encoding a long non-coding RNA FMR1 antisense RNA 1
• FRMPD3: encoding protein FERM and PDZ domain containing 3
• FUNDC1: encoding protein FUN14 domain containing 1
• FUNDC2: FUN14 domain-containing protein 2
• GATA1: encoding GATA1 transcription factor
• GNL3L encoding protein G protein nucleolar 3 like
• GPRASP2: G-protein coupled receptor-associated sorting protein 2
• GRIPAP1: encoding protein GRIP1-associated protein 1
• HDHD1A: encoding enzyme Haloacid dehalogenase-like hydrolase domain-containing protein 1A
• LAS1L encoding protein LAS1-like protein
• MAGEA2: encoding protein Melanoma-associated antigen 2
• MAGEA5 encoding protein Melanoma antigen family A, 5
• MAGEA8: encoding protein Melanoma antigen family A, 8
• MAGED4B: encoding protein Melanoma-associated antigen D4
• MAGT1: encoding protein Magnesium transporter protein 1
• MBNL3: encoding protein Muscleblind-like protein 3
• MIR222: encoding microRNA MicroRNA 222
• MIR361: encoding microRNA MicroRNA 361
• MIR660: encoding protein MicroRNA 660
• MORF4L2: encoding protein Mortality factor 4-like protein 2
• MOSPD1: encoding protein Motile sperm domain containing 1
• MOSPD2: encoding protein Motile sperm domain containing 2
• NKRF: encoding protein NF-kappa-B-repressing factor
• NRK: encoding enzyme Nik-related protein kinase
• OTUD5: encoding protein OTU deubiquitinase 5
• PASD1: encoding protein PAS domain-containing protein 1
• PAGE1 :encoding a protein of unestablished function
• PBDC1: encoding a protein of unestablished function
• PCYT1B: encoding enzyme Choline-phosphate cytidylyltransferase B
• PIN4: encoding enzyme Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4
• PLAC1: encoding protein Placenta-specific protein 1
• PLP2: encoding protein Proteolipid protein 2
• RPA4: encoding protein Replication protein A 30 kDa subunit
• RPS6KA6: encoding protein Ribosomal protein S6 kinase, 90kDa, polypeptide 6
• RRAGB: encoding protein Ras-related GTP-binding protein B
• SFRS17A: encoding protein Splicing factor, arginine/serine-rich 17A
• SLITRK2: encoding protein SLIT and NTRK-like protein 2
• SMARCA1: encoding protein Probable global transcription activator SNF2L1
• SMS: encoding enzyme Spermine synthase
• SSR4: encoding protein Translocon-associated protein subunit delta
• TAF7l: encoding protein TATA-box binding protein associated factor 7-like
• TCEAL1: encoding protein Transcription elongation factor A protein-like 1
• TCEAL4: encoding protein Transcription elongation factor A protein-like 4
• THOC2: encoding protein THO complex subunit 2
• TMEM29: encoding protein Protein FAM156A
• TMEM47: encoding protein Transmembrane protein 47
• TMLHE: encoding enzyme Trimethyllysine dioxygenase, mitochondrial
• TNMD encoding protein Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM)
• TRAPPC2P1 encoding protein Trafficking protein particle complex subunit 2
• TREX2: encoding enzyme Three prime repair exonuclease 2
• TRO: encoding protein Trophinin
• TSPYL2: encoding protein Testis-specific Y-encoded-like protein 2
• USP51: encoding enzyme Ubiquitin carboxyl-terminal hydrolase 51
• YIPF6: encoding protein Protein YIPF6
• ZC3H12B: encoding protein ZC3H12B
• ZFP92: encoding protein ZFP92 zinc finger protein
• ZMYM3: encoding protein Zinc finger MYM-type protein 3
• ZNF157: encoding protein Zinc finger protein 157
• ZNF182 encoding protein Zinc finger protein 182
• ZNF275: encoding protein Zinc finger protein 275
• ZNF674: encoding protein Zinc finger protein 674

Structure

It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments. 

The X chromosome is notably larger and has a more active euchromatin region than its Y chromosome counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease. 

It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human testis (in healthy patients).

Role in diseases

Numerical abnormalities

Klinefelter syndrome:

• Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone.
• Males with Klinefelter syndrome typically have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). It is less common for affected males to have two or three extra X chromosomes (48,XXXY or 49,XXXXY) or extra copies of both the X and Y chromosomes (48,XXYY) in each cell. The extra genetic material may lead to tall stature, learning and reading disabilities, and other medical problems. Each extra X chromosome lowers the child's IQ by about 15 points,^[20][21] which means that the average IQ in Klinefelter syndrome is in general in the normal range, although below average. When additional X and/or Y chromosomes are present in 48,XXXY, 48,XXYY, or 49,XXXXY, developmental delays and cognitive difficulties can be more severe and mild intellectual disability may be present.
• Klinefelter syndrome can also result from an extra X chromosome in only some of the body's cells. These cases are called mosaic 46,XY/47,XXY.

Triple X syndrome (also called 47,XXX or trisomy X):

• This syndrome results from an extra copy of the X chromosome in each of a female's cells. Females with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. The average IQ of females with this syndrome is 90, while the average IQ of unaffected siblings is 100. Their stature on average is taller than normal females. They are fertile and their children do not inherit the condition.
• Females with more than one extra copy of the X chromosome (48, XXXX syndrome or 49, XXXXX syndrome) have been identified, but these conditions are rare.

Turner syndrome:

• This results when each of a female's cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the features of the condition, including short stature and infertility.
• About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in a woman's body has only one copy of the X chromosome instead of the usual two copies. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely missing. Some women with Turner syndrome have a chromosomal change in only some of their cells. These cases are called Turner syndrome mosaics (45,X/46,XX).

X-linked recessive disorders

Sex linkage was first discovered in insects, e.g., T. H. Morgan's 1910 discovery of the pattern of inheritance of the white eyes mutation in Drosophila melanogaster. Such discoveries helped to explain x-linked disorders in humans, e.g., haemophilia A and B, adrenoleukodystrophy, and red-green color blindness.

Other disorders

XX male syndrome is a rare disorder, where the SRY region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.

X-linked endothelial corneal dystrophy is an extremely rare disease of cornea associated with Xq25 region. Lisch epithelial corneal dystrophy is associated with Xp22.3. 

Megalocornea 1 is associated with Xq21.3-q22

Adrenoleukodystrophy, a rare and fatal disorder that is carried by the mother on the x-cell. It affects only boys between the ages of 5 and 10 and destroys the protective cell surrounding the nerves, myelin, in the brain. The female carrier hardly shows any symptoms because females have a copy of the x-cell. This disorder causes a once healthy boy to lose all abilities to walk, talk, see, hear, and even swallow. Within 2 years after diagnosis, most boys with Adrenoleukodystrophy die.

Role in mental abilities and intelligence

The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions. In other words, a significant proportion of genes associated with intelligence is passed on to the male offspring from the maternal side and to the female offspring from either/both maternal and paternal side. There has also been interest in the possibility that haploinsufficiency for one or more X-linked genes has a specific impact on development of the Amygdala and its connections with cortical centres involved in social–cognition processing or the ‘social brain'.

X-linked dominant inheritance

From Wikipedia, the free encyclopedia

 

X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected.

X-linked dominant traits do not necessarily affect males more than females (unlike X-linked recessive traits). The exact pattern of inheritance varies, depending on whether the father or the mother has the trait of interest. All fathers that are affected by an X-linked dominant disorder will have affected daughters but not affected sons. However, if the mother is also affected then sons will have a chance of being affected, depending on whether a dominant or recessive X chromosome is passed on. When the son is affected, the mother will always be affected.

Some scholars have suggested discontinuing the terms dominant and recessive when referring to X-linked inheritance due to the multiple mechanisms that can result in the expression of X-linked traits in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion and somatic mosaicism.

Genetics

As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the sex of the parent carrying a specific gene and can often seem complex. This is due to the fact that, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.

Males can only get an X chromosome from their mother whilst females get an X chromosome from both parents. As a result, females tend to show higher prevalence of X-linked dominant disorders because they have more of a chance to inherit a faulty X chromosome.

Inheritance

X-linked dominant inheritance works differently depending upon whether the mother (left image) or father (right image) is the carrier of a gene that causes a disease or disorder.

In X-linked dominant inheritance, when the mother alone is the carrier of a mutated, or defective gene associated with a disease or disorder; she herself will have the disorder. Her children will inherit the disorder as follows:

• Of her daughters and sons: 50% will have the disorder, 50% will be completely unaffected. Children of either sex have an even chance of receiving either of their mother's two X chromosomes, one of which contains the defective gene in question.

When the father alone is the carrier of a defective gene associated with a disease or disorder, he too will have the disorder. His children will inherit the disorder as follows:

• Of his daughters: 100% will have the disorder, since all of his daughters will receive one copy of his single X chromosome.
• Of his sons: none will have the disorder; sons do not receive an X chromosome from their father.

If both parents were carriers of a defective gene associated with a disease or disorder, they would both have the disorder. Their children would inherit the disorder as follows:

• Of their daughters: 100% will have the disorder, since all of the daughters will receive a copy of their father's X chromosome.
• Of the sons: 50% will have the disorder, 50% will be completely unaffected. Sons have an equal chance of receiving either of their mother's X chromosomes.

In such a case, where both parents carry and thus are affected by an X-linked dominant disorder, the chance of a daughter receiving two copies of the X chromosome with the defective gene is 50%, since daughters receive one copy of the X chromosome from both parents. Were this to occur with an X-linked dominant disorder, that daughter would likely experience a more severe form. 

Some X-linked dominant conditions such as Aicardi syndrome are fatal to boys, therefore only girls with these conditions survive, or boys with Klinefelter's syndrome (and hence have more than one X chromosome).

List of dominant X-linked diseases

• Vitamin D resistant rickets: X-linked hypophosphatemia
• Rett syndrome (95% of cases are due to sporadic mutations)
• Most cases of Alport syndrome
• Incontinentia pigmenti
• Giuffrè–Tsukahara syndrome
• Goltz syndrome
• X-linked dominant porphyria
• Fragile X syndrome

Anticipation (genetics)

From Wikipedia, the free encyclopedia

 

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

Trinucleotide repeats and expansion

Trinucleotide repeats are apparent in a number of loci in the human genome. They have been found in introns, exons and 5' or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis, unstable repeats can undergo triplet expansion (see later section); in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues. 

The mechanism behind the expansion of the triplet repeats is not well understood. One hypothesis is that the increasing number of repeats influence the overall shape of the DNA, which can have an effect on its interaction with DNA polymerase and thus the expression of the gene.

Disease mechanisms

For many of the loci, trinucleotide expansion is harmless, but in some areas expansion has detrimental effects that cause symptoms. When the trinucleotide repeat is present within the protein-coding region, the repeat expansion leads to production of a mutant protein with gain of function. This is the case for Huntington's disease, where the trinucleotide repeat encodes a long stretch of glutamine residues. When the repeat is present in an untranslated region, it could affect the expression of the gene in which the repeat is found (ex. fragile X) or many genes through a dominant negative effect (ex. myotonic dystrophy). 

In order to have a deleterious effect, the number of repeats must cross a certain threshold. For example, normal individuals have between 5 and 30 CTG repeats within the 3' UTR of DMPK, the gene that is altered in myotonic dystrophy. If the number of repeats is between 50 to 100, the person is only mildly affected – perhaps having only cataracts. However, meiotic instability could result in a dynamic mutation that increases the number of repeats in offspring inheriting the mutant allele. Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe – including electrical myotonia. As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.

Examples of diseases showing anticipation

Diseases showing anticipation include:

• Autosomal dominant
  • Several spinocerebellar ataxias
  • Huntington's disease – CAG
  • Myotonic dystrophy – CTG
  • Dyskeratosis congenita – TTAGGG (telomere repeat sequence)
• Autosomal recessive
  • Friedreich ataxia – GAA (Note: Friedreich ataxia does not usually exhibit anticipation because it is an autosomal recessive disorder.)
• X-linked
  • Fragile X syndrome – CGG
• Without expression type
  • Crohn's disease
  • Behçet's disease

Fragile X syndrome

From Wikipedia, the free encyclopedia

 

Fragile X syndrome
Other names	Martin-Bell syndrome, Escalante syndrome
Boy with fragile X syndrome
Specialty	Medical genetics, pediatrics, psychiatry
Symptoms	Intellectual disability, long and narrow face, large ears, flexible fingers, large testicles
Complications	Autism features, seizures
Usual onset	Noticeable by age 2
Duration	Lifelong
Causes	Genetic (X-linked dominant)
Diagnostic method	Genetic testing
Treatment	Supportive care, early interventions
Frequency	1 in 4,000 (males), 1 in 8,000 (females)

Fragile X syndrome (FXS) is a genetic disorder. Symptoms often include mild to moderate intellectual disability. The average IQ in males is under 55, while about two thirds of females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common and seizures occur in about 10%. Males are usually more affected than females.

Fragile X syndrome is inherited in an X-linked dominant pattern. Women with a premutation have an increased risk of having an affected child. It is typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. This results in not enough of the fragile X mental retardation protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene. Normal is between 5 and 40 repeats, fragile X syndrome occurs with more than 200, and a premutation is said to be present when an intermediate number of repeats occurs. Testing for premutation carriers may allow for genetic counseling.

There is no cure. Early intervention is recommended as it provides the most opportunity for developing a full range of skills. These interventions may include special education, speech therapy, physical therapy, or behavioral therapy. Medications may be used to treat associated seizures, mood problems, aggressive behavior, or ADHD. Fragile X syndrome is estimated to occur in 1.4 in 10,000 males and 0.9 in 10,000 females.

Signs and symptoms

Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.

 

Most young children do not show any physical signs of FXS. It is not until puberty that physical features of FXS begin to develop. Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with fragile X syndrome also meet the diagnostic criteria for autism. 

Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.

Physical phenotype

• Large, protruding ears (both)
• Long face (vertical maxillary excess)
• High-arched palate (related to the above)
• Hyperextensible finger joints
• Hyperextensible ('double-jointed') thumbs
• Flat feet
• Soft skin
• Postpubescent macroorchidism (large testicles in men after puberty)
• Hypotonia (low muscle tone)

Intellectual development

Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene. Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively spared.

Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children.

When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.

Autism

Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD.

Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to severe ASD. When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.

Genetic mouse models of FXS have also been shown to have autistic-like behaviors.

Social interaction

FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.

It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder.

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety. 

Individuals with FXS show decreased activation in the prefrontal regions of the brain.

Mental health

Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS. Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong.

Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the child's sensitivity in some cases. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety. 

Perseveration is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches. Although only a minority of FXS cases will meet the criteria for obsessive–compulsive disorder (OCD), a significant majority will have symptoms of obsession. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors.

Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.

Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience combinations of dementia, mood, and anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism.

Vision

Ophthalmologic problems include strabismus. This requires early identification to avoid amblyopia. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common.

Neurology

Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. In larger study populations the frequency varies between 13% and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication.

Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease. It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline.

Working memory

From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.

Fertility

About 20% of women who are carriers for the fragile X premutation are affected by fragile X-related primary ovarian insufficiency (FXPOI), which is defined as menopause before the age of 40. The number of CGG repeats correlates with penetrance and age of onset. However premature menopause is more common in premutation carriers than in women with the full mutation, and for premutations with more than 100 repeats the risk of FXPOI begins to decrease. Fragile X-associated primary ovarian insufficiency (FXPOI) is one of three Fragile X-associated Disorders (FXD) caused by changes in the FMR1 gene. FXPOI affects female premutation carriers of Fragile X syndrome, which is caused by the FMR1 gene, when their ovaries are not functioning properly. Women with FXPOI may develop menopause-like symptoms but they are not actually menopausal. Women with FXPOI can still get pregnant in some cases because their ovaries occasionally release viable eggs.

FMRP is a chromatin-binding protein that functions in the DNA damage response. FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.

Causes

Location of FMR1 gene on the X chromosome.

 

Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.

In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. Between 45-54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 CGG repeats. In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product.

This methylation of FMR1 in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name. One study found that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex.

A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in FMR1. This subset lacked the CGG repeat expansion in FMR1 traditionally associated with fragile x syndrome.

Inheritance

Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive. Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.

Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring. This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985. Due to this, male children often have a greater degree of symptoms than their mothers.

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm. Incidentally, males with a full mutation only pass on premutations to their daughters. However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected. In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis.

Pathophysiology

FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning. Connectome changes have long been suspected to be involved in the sensory pathophysiology and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. The downregulation of GABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.

Diagnosis

Cytogenetic analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome. This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individual's cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised. 

Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using Southern blot analysis. By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1 will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS. 

Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.

Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children or fetuses with the syndrome, and allowing genetic counselling with regards to the potential for a couple's future children to be affected. Most parents notice delays in speech and language skills, difficulties in social and emotional domains as well as sensitivity levels in certain situations with their children.

Management

There is no cure for the underlying defects of FXS. Management of FXS may include speech therapy, behavioral therapy, sensory integration occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.

Medication

Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as risperidone and quetiapine are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%–18% of individuals suffering from FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS. Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Few studies suggested using folic acid, but more researches are needed due to the low quality of that evidence. Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS. While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms.

Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor.

ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.

Prognosis

A 2013 review stated that life expectancy for FXS was 12 years lower than the general population and that the causes of death were similar to those found for the general population.

Research

Fragile X syndrome is the most translated neurodevelopmental disorder under study. The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of arbaclofen, a GABA_B agonist, in improving social withdrawal in individuals with FXS and ASD.

In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from controlled trials to support its use.

The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.

History

In 1943, James Purdon Martin and Julia Bell described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz outlined extensively the physical, psychological, and cytogenic characteristics of those afflicted in addition to prospects for therapy. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.