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

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.

Prevalence of cytogenetic abnormalities and FMR1 gene premutation in a Portuguese population with premature ovarian insufficiency

“…30 This is in line with a previous study involving almost 135 000 women from an unselected pan-ethnic cohort, which also reported a lower incidence of FMR1-PM in Asian patients. 41 In accordance with other studies, the prevalence was higher in familial cases of POI (13.6% vs 4.5%). 5,14,26 The fact that this difference was not statistically significant in our sample may also be attributed to the small sample size.…”

Development of Chinese genetic reference panel for Fragile X Syndrome and its application to the screen of 10,000 Chinese pregnant women and women planning pregnancy

“…The frequency of fragile X carriers was found to be 1/883 and the frequency of premutation alleles was 1/2650 among 2,650 pregnant women in Hong Kong, China (Cheng et al, 2017). In a recent large‐scale fragile X carrier screening report in the United States, the frequency of premutation carriers among those that self‐reported as Asian reached 1/419 (20/7961) in a large, ethnically diverse population referred for carrier testing (Owens et al, 2018). We previously reported the CGG repeat pattern and the FMR1 haplotype in 1,113 Chine Han subjects and found one female carrier of a premutation allele (Huang et al, 2015).…”

“…The fragile X premutation frequency in females is very high: estimates have reached 1/130 to 1/260 in European and American populations (Hantash et al, 2011; Hunter et al, 2014; Maenner et al, 2013; Seltzer et al, 2012; Yrigollen et al, 2012). However, the rate is ~ 1/400 in Chinese American population (Owens et al, 2018). Approximately one third of premutation males and a small number of females will develop Fragile X–associated tremor/ataxia syndrome after age 50 (Berry‐Kravis et al, 2007; Hagerman & Hagerman, 2016), and approximately 20% of female premutation carriers will develop fragile X–associated primary ovarian insufficiency (Allen et al, 2007; Sherman, 2000).…”

“…The frequency of female fragile X carriers is relatively high; however, prevalence varies based on ethnic differences (Crawford, Acuna, & Sherman, 2001; Owens et al, 2018; Seltzer et al, 2012). Currently, there is no large‐scale epidemiological survey data from China.…”

Zebrafish Chromosome 14 Gene Differential Expression in the fmr1hu2787 Model of Fragile X Syndrome

“…Fragile X Syndrome (FXS) is an X-chromosome-linked form of human inherited intellectual disability affecting, on a panethnic basis, approximately 1 in every 2,400 male foetuses (Owens et al, 2018) (As females are diploid for the X-chromosome, the proportion of female foetuses affected is far lower). FXS most commonly arises due to expansion of a CGG trinucleotide repeat sequence in the human FMR1 gene that codes for an RNA-binding protein involved in multiple aspects of RNA metabolism (Salcedo-Arellano et al, 2020).…”