FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing

Am J Med Genet A. 2018 Jun;176(6):1304-1308. doi: 10.1002/ajmg.a.38692. Epub 2018 Mar 31.

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine-guanine-guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55-200 CGG repeats) are at risk to have an affected child. Currently, specific population-based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan-ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self-reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan-ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan-ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic-based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population-wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population-wide screening recommendations for FXS.

Keywords: carrier frequency; carrier screening; fragile X syndrome; premutation allele.

MeSH terms

  • Cohort Studies
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / ethnology
  • Fragile X Syndrome / genetics*
  • Gene Frequency
  • Genetic Carrier Screening
  • Humans
  • Mutation Rate*
  • Retrospective Studies
  • Trinucleotide Repeat Expansion

Substances

  • FMR1 protein, human
  • Fragile X Mental Retardation Protein