High Throughput Evidence Generation to Support Tentative Gene Disease Relationship from A Cohort Enriched for Autozygosity and Founder Effect.

Abstract

Gene-disease relationship (GDR) is a key concept in monogenic disease diagnostics. While functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to support or challenge proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort comprised primarily of Mendelian phenotypes and enriched for consanguinity and founder effect can accelerate evidence generation by enabling high throughput discovery of homozygous loss of function (LOF) variants as well as strong segregation data. To test this hypothesis, we analyzed our Lifera Omics Database (LODB) for homozygous high impact missense variants that are observed in two or more unrelated individuals to exploit the power of founder variants, as well as homozygous presumptive LOF. The search spanned 2,904 genes with tentative GDR in the literature. The analysis revealed 154 individuals with 119 homozygous LOF variants that support GDR for 95 genes. Additionally, we identified 13 founder missense variants (33 homozygous individuals) that support GDR for 13 genes. Our data expand the mode of inheritance (MOI) of 19 genes for which the tentative GDR was based on dominant variants. Phenotypic expansion was encountered in 18 of the supported GDR including those in which the full syndromic constellation has not been previously delineated. We also report 4 novel allelic disorders of reported GDR. This work highlights the potential of diagnostic labs to accelerate GDR refinement through data sharing and working closely with the referring physicians. It also showcases the added advantage concerning autosomal recessive GDR when the study population is enriched for consanguinity and founder effect.