An Elevated Birth Prevalence of Fraser Syndrome in Quebec Linked To A Founder Pathogenic Variant

Abstract

PurposeFraser syndrome (FS) is an autosomal recessive disorder, characterized by cryptophthalmos, syndactyly, and anomalies of the respiratory and urogenital tracts. Here we estimate the birth prevalence of FS in the French-Canadian founder population of Quebec, where no prevalence has been reported to date. We also describe the phenotype of probands with FS. MethodsPathogenic allele frequency was estimated in the Quebec IBD cohort and the population-based cohort CARTaGENE (CaG), from exome sequencing (n=2,323), short-read genome sequencing (n=2,173) and genotyping array data (n=29,330). Phenotypic data was collected for FS probands at CHU Ste-Justine (between 2013 and 2023). ResultsFRAS1 p.(Arg124Ter) was the most frequent pathogenic variant in the Quebec IBD and CaG cohorts, with frequencies 17-fold and 21-fold higher than Non-Finnish Europeans. Four French-Canadian probands were diagnosed with FS at CHU Ste-Justine, three of whom were homozygous for the variant. Birth prevalence was 0.23 per 100,000 births when predicted from the Quebec IBD cohort, 0.98 from CaG, and 1.34 from reported cases. ConclusionFS shows an elevated birth prevalence in the French-Canadian population of Quebec. We propose FRAS1 p.(Arg124Ter) as a candidate founder pathogenic variant, informing clinical practices in this population.