FMR1 allele size distribution in 35,000 males and females: a comparison of developmental delay and general population cohorts

Purpose: Developmental delay phenotypes have been associated with FMR1 premutation (PM: 55–200 CGG repeats) and “gray zone” (GZ: 45–54 CGG repeats) alleles. However, these associations have not been confirmed by larger studies to be useful in pediatric diagnostic or screening settings. Methods: This study determined the prevalence of PM and GZ alleles in two independent cohorts of 19,076 pediatric referrals to developmental delay diagnostic testing through Victorian Clinical Genetics Service (cohort 1: N = 10,235; cohort 2: N = 8841), compared with two independent general population cohorts (newborn screening N = 1997; carrier screening by the Victorian Clinical Genetics Service prepair program N = 14,249). Results: PM and GZ prevalence rates were not significantly increased (p > 0.05) in either developmental delay cohort (male PM: 0.12–0.22%; female PM: 0.26–0.33%; male GZ: 0.68–0.69%; female GZ: 1.59–2.13-%) compared with general population cohorts (male PM: 0.20%; female PM: 0.27–0.82%; male GZ: 0.79%; female GZ: 1.43–2.51%). Furthermore, CGG size distributions were comparable across datasets, with each having a modal value of 29 or 30 and ~1/3 females and ~1/5 males having at least one allele with ≤26 CGG repeats. Conclusion: These data do not support the causative link between PM and GZ expansions and developmental-delay phenotypes in pediatric settings.