A 3-year-old boy is brought to the office for follow-up on intellectual disability and speech delay. Review of his developmental screening questionnaire shows that the boy does not imitate his parents' activities, have a social smile, or show interest in other children. The patient has 8-10 words in his vocabulary and does not combine them into 2-word phrases. There is also concern that his verbal comprehension is poor; a subsequent audiologic evaluation was normal. The boy is up to date on all vaccinations and has no other significant medical history. Cytogenetic testing reveals 226 CGG trinucleotide repeats in a gene located on the X chromosome. This anomaly results in the patient's clinical condition through which of the following mechanisms?
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This patient with developmental delay and a trinucleotide expansion on chromosome X has fragile X syndrome (FXS), one of the most common causes of intellectual disability. FXS is caused by a mutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene on the long arm of the X chromosome.
FMR1 normally has 6 to 50 CGG trinucleotide repeats in the 5′ untranslated region that can potentially expand during meiosis in oocytes. Expansion over generations can lead to >200 CGG trinucleotide repeats (ie, full mutation), which causes FMR1 hypermethylation. DNA methylation in the promoter region of FMR1 prevents transcription of the gene and subsequent production of fragile X messenger ribonucleoprotein (FMRP).
Because FMRP is involved in development and plasticity of neurons, silencing of the gene in FXS results in impaired neural development. Early findings include developmental delay and neurobehavioral features (eg, attention deficit hyperactivity disorder, autism spectrum disorder), as seen in this patient with speech delay and poor social skills. Physical findings of FXS are subtle until puberty, at which time macroorchidism and dysmorphic facies (eg, long, narrow face; prominent forehead and chin) become more noticeable.
(Choice A) Imprinting refers to physiologic gene expression from only 1 parental allele rather than from both. Disease occurs when there is a deletion of the allele that is normally expressed, as in Prader-Willi syndrome (paternally inherited deletion of part of chromosome 15). The severity of FXS depends on the number of trinucleotide repeats or sex of the patient (ie, boys have more severe presentations), not the parental origin of the mutation.
(Choice B) Defects in DNA mismatch repair genes cause Lynch syndrome, a condition with an increased risk of hereditary nonpolyposis colorectal cancer and extraintestinal malignancies. Although mismatch repair may have a role in expanding trinucleotide repeats over successive generations, clinical features of FXS do not occur without hypermethylation-induced silencing of FMR1.
(Choices C and D) Exons (expressed codons) are protein coding regions of DNA. Introns are removed during intranuclear mRNA processing and not expressed in the final mRNA sequence. Abnormalities in exon deletion or intron splicing generally result in a nonfunctional protein, whereas in FXS gene hypermethylation prevents transcription and translation.
Educational objective:
Fragile X syndrome is caused by increased CGG trinucleotide repeats within the fragile X messenger ribonucleoprotein 1 (FMR1) gene on the long arm of the X chromosome. This leads to hypermethylation and silencing of FMR1.