Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases

Likely pathogenic variants were detected in eight candidate genes, namely homozygous or compound heterozygous variants in three autosomal genes (ADAMTSL2, NALCN, VPS13B), one in an X-linked gene (MID1), and de novo heterozygous variants in four autosomal genes (RYR2, GABBR2, CDK13, DDX3X). Two patients harbored rare variants in two or more candidate genes, while in three other patients no candidate was identified. In five probands (62%), the detected variants explained their clinical findings. The causative recessive variants would have led to diagnosis even without parental exome sequencing, but for the heterozygous dominant ones, the exome trio-based approach was fundamental in the identification of the de novo likely pathogenic variants.