A 25-year-old man with a history of autism and mental retardation is seen by a genetic counselor. The man has coarse facial features, an increased head circumference, and macro-orchidism. His maternal uncle is similarly affected. After further evaluation, a diagnosis of fragile X syndrome is rendered. What is the most likely underlying cause of this patient's genetic disease?
Fragile X syndrome, the most common cause of inherited mental retardation, is caused by expansion of a CGG trinucleotide repeat in a noncoding region immediately adjacent to the FMR1 gene on the X chromosome. In a poorly understood manner, the expanded CGG repeat silences the FMR1 gene by methylation of its promoter. The abnormal repeat is associated with an inducible "fragile site" on the X chromosome, which appears in cytogenetic studies as a nonstaining gap or chromosomal break. The male newborn afflicted with the fragile X syndrome appears normal, but during childhood, characteristic features appear, including an increased head circumference, facial coarsening, joint hyperextensibility, enlarged testes, and abnormalities of the cardiac valves. Mental retardation is profound, with IQ scores varying from 20 to 60. A significant proportion of autistic male children carry a fragile X chromosome. The other choices do not cause fragile X syndrome.Diagnosis: Fragile X syndrome
Chromosomal nondisjunction
Chromosome inversion
Expansion of trinucleotide repeat
Frame-shift mutation
Genetics