Gene–disease relationship (GDR) is a key concept in monogenic disease diagnostics. Although functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to supporting or challenging a proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort composed 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.