Fragile X syndrome
Fragile X syndrome (FXS), also known as Martin-Bell syndrome or Escalante's syndrome, is a genetic syndrome but not one usually associated with single nucleotide mutations. Nearly half of all children with fragile X syndrome meet the criteria for a diagnosis of autism. It is an inherited cause of intellectual disability especially among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and large testicles (macroorchidism), and behavioral characteristics such as stereotypic movements (e.g. hand-flapping), and social anxiety.Wikipedia
in 99% of cases, Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP) required for normal neural development. Note that repeat expansions are *not* typically assayed by common genotyping platforms such as the DNA chips used by AncestryDNA, 23andMe and similar companies.Wikipedia
Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome). A definitive diagnosis of fragile X syndrome is made through genetic testing to determine the number of CGG repeats.Wikipedia
Most individuals with the premutation do not have cognitive deficits; however, some with high repeat sizes (>100 repeats) have been identified with learning difficulties, emotional problems, or even intellectual disability. Females with premutations (usually >80 CGG repeats) are at ~20% risk for premature ovarian insufficiency (POI), a condition referred to as FXPOI. Older males and females with premutations are at risk for FXTAS, a late-onset, progressive development of intention tremor and ataxia often accompanied by progressive cognitive and behavioral difficulties including memory loss, anxiety, reclusive behavior, deficits of executive function, and dementia. The risk for FXTAS is higher in males who carry a premutation as compared with females. The penetrance of FXTAS increases with age and with premutation repeat length.[PMID 23765048]
Inheritance of the FMR1 mutation is X-linked, although the pattern of fragile X syndrome is complicated due to the characteristics of the unstable repeat sequence mutation. In typical fragile X families, the mutation is a multistep expansion occurring over one or more generations in a region of CGG repeats in the 5′ untranslated region of the gene. With extremely rare exceptions, the parent of origin of the expansion from a premutation to the full mutation is female.[PMID 23765048]
For more information on these disorders, see the online GeneReviews profile for FMR1-related disorders at http://www.ncbi.nlm.nih.gov/sites/GeneTests/ and the National Fragile X Foundation at http://www.nfxf.org.