FMR1 Premutation Carrier Frequency in Patients Undergoing Routine Population-Based Carrier Screening: Insights Into the Prevalence of Fragile X Syndrome, Fragile X-Associated Tremor/Ataxia Syndrome, and Fragile X-Associated Primary Ovarian Insufficiency in the United States

Fragile X syndrome (FXS), the most common inherited cause of mental retardation, is caused by the expansion and methylation of the triplet nucleotide CGG in the 5′ untranslated region of the FMR1 gene on the X chromosome. Expanded FMR1 CGG alleles are defined as premutations (55–200 repeats) or full mutations (>200 repeats). Individuals who carry premutation alleles are considered carriers, whereas males with full mutations are affected with FXS. Although generally considered normal, males who carry premutations are at risk for a late-onset ataxia/tremor syndrome, and females with premutations are at risk for premature ovarian failure. Previous studies estimating premutation and full mutation carrier frequencies show differences among various populations and countries. Two prior studies estimated the premutation carrier frequency in the United States to be between 1:257 and 1:382, but these may be overestimates because of bias toward detecting higher frequencies. Such bias can occur through inclusion of self-paying patients (more affluent patients) and patients with learning disabilities, mental retardation, developmental delay, or those with a family history of FXS. Until recently, technical barriers prevented pilot studies to assess feasibility of population-based carrier screening and newborn screening for FXS. The aim of this study was to estimate the frequency of FXS premutation and full mutation alleles among nonselected, unbiased populations in the United States. Samples of deoxyribonucleic acid (DNA) were obtained from 2 populations undergoing routine carrier screening for other genetic diseases. The first was a series of 11,759 cystic fibrosis carrier screening samples and the second included 2011 samples from the Ashkenazi Jewish population (submitted for screening for genetic diseases). A validated laboratory-developed test using triplet-primed polymerase chain reaction was used to detect premutation and full mutation alleles in the DNA samples. Among the cystic fibrosis DNA screening samples, 48 premutations were identified (carrier frequency, 1:245); there were 15 premutations identified in DNA samples from the Ashkenazi Jewish population (carrier frequency, 1:134). Adjusting for the ethnic mix in the screening population provided a better estimate of the female premutation carrier frequency in the United States (1:178). Using this female premutation frequency in conjunction with Hagerman equations to account for likelihood of expansion to full mutations, the calculated full mutation frequency in the US population (males and females) was 1:3335 and the calculated premutation frequency in males was 1:400. Based on these estimates, the calculated frequency of fragile X-associated tremor and ataxia syndrome was 1:4848 in males and the carrier frequency of fragile X-associated primary ovarian insufficiency in females was 1:3560. These findings suggest that population-based carrier screening for FXS in the United States may be feasible and warranted based on the carrier rate of this syndrome, provided that ethical and social concerns can be addressed.