Population Prevalence of Deleterious Variants.

BACKGROUND

Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of -linked M-D is unknown, the pathogenicity of variants identified in patients with M-D may be indeterminant, and variants predicted to be deleterious by analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.

METHODS

variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated pathogenic variants.

RESULTS

Within gnomAD v2, there were 56, 408, and 1250 alleles harboring variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an variant with a CADD score ≥ 25.

DISCUSSION

M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.

HIGHLIGHTS

analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.