FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

Abstract

BackgroundPopulation screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US.MethodsBlood spot screening of 14,207 newborns (7,312 males and 6,895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach.ResultsThe prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats).ConclusionsThe presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported.

Distribution of AGG interruption patterns within nine world populations

“…The remaining samples were recruited from high-risk populations including intellectual disabilities, individuals with a family history of FXS and individuals with Parkinsonism. DNA isolation and AGG interruption genotyping were performed at the UC Davis MIND Institute Molecular Laboratory as previously described (25,32), except 67 alleles extracted and genotyped in Italy, following IRB approved protocols at the correspondent institutions. Only AGG interruption patterns of unrelated normal alleles less than or equal to 40 CGG repeats in length, therefore within the normal size range (33)(34)(35), were included in the study.…”

Fragile X spectrum disorders

“…The rate of FMR1 gray zone expansions in the general population is variable, but large population studies report rates of 0.8% to 3.0% for repeat sizes between 41 and 54 (138)(139)(140). In 2006, it was recognized that gray zone expansion carriers can also present with premature ovarian insufficiency at a higher rate that in the general population (141,142).…”

“…Since the prevalence of the premutation is much higher (1 in 130-250 females and 1 in 250-810 males) (27) than those with the full mutation (1 in 4,000-7,000) the impact of multiple medical and neurological problems in premutation carriers is far more significant in the population than the full mutation (28,29). The association of other disorders in adults with the premutation led to multiple studies in children and here we present a review of the manifestations in children with FXSD.…”

“It gives them more options”: preferences for preconception genetic carrier screening for fragile X syndrome in primary healthcare

“…As such, FXS carrier screening, either stand-alone or as part of expanded screening, provides a useful model through which to consider carrier screening approaches because of the complexity and duality of risk information provided (Henneman et al 2016). As outlined by Hill et al (2010), arguments for carrier screening for FXS include a high prevalence (which may be up to 1 in 2500 in males and females (Hagerman 2008)) and high carrier frequency (recently reported to be 1 in 179 estimated for North American populations (Hantash et al 2011)), the prevalence of premutation alleles estimated as 1:209 in females and 1:430 in males (Tassone et al 2012), and an accurate testing method amenable to screening populations (Tassone et al 2008) which identifies an expanded CGG repeat in the FMR1 gene (the cause of FXS in over 99 % of cases). In addition, the condition is well understood and defined; there are a range of significant phenotypic effects associated with the full mutation (FM ≥200 hypermethylated CGG repeats) including intellectual disability and cognitive, behavioral, and medical problems, which have a substantial impact on the affected individual and their family (Hagerman and Hagerman 2002).…”