Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan

Intellectual disability (ID) is a neurodevelopmental disorder affecting up to 1-3% of people worldwide. Genetic factors, including rare de novo or rare homozygous mutations, explain many cases of autosomal dominant or recessive forms of ID. ID is clinically and genetically heterogeneous, with hundreds of genes associated with it. In this study, we performed high-depth whole-genome sequencing of twenty individuals from five consanguineous families from Pakistan, with nine individuals affected by mild or severe ID. We identified one splice and five missense rare variants (at allele frequencies below 0.001%) in a homozygous state in the affected individuals with supporting and moderate evidence of pathogenicity based on guidance from the American College of Medical Genetics and Genomics. These six variants mapped to different genes (SRD5A3, RDH11, RTF2, PCDHA2, ADAMTS17, and TRPC3), and only SRD5A3 had previously been known to cause ID. The p.Tyr169Cys mutation inside SRD5A3 was predicted to be deleterious and affect protein structure by multiple in silico tools. In addition, we found one missense mutation, p.Pro1505Ser, inside UNC13B with conflicting evidence of pathogenic and benign effects. Further functional studies are required to confirm the pathogenicity of these variants and understand their role in ID. Our findings provide additional needed information for interpreting rare variants in the genetic testing of ID.