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

Thaise NR Carneiro,1 Ana CV Krepischi,1 Silvia S Costa,1 Israel Tojal da Silva,2 Angela M Vianna-Morgante,1 Renan Valieris,2 Suzana AM Ezquina,1 Debora R Bertola,3 Paulo A Otto,1 Carla Rosenberg1 1Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; 2Laboratory of Computational Biology and Bioinformatics, International Research Center, A. C. Camargo Cancer Center, São Paulo, Brazil; 3Genetics Unit, Instituto da Criança, Hospital das Clínicas, Medical School, University of São Paulo, São Paulo, Brazil Introduction: Exome sequencing is recognized as a powerful tool for identifying the genetic cause of intellectual disability (ID). It is uncertain, however, whether only the exome of the proband should be sequenced or if the sequencing of parental genomes is also required, and the resulting increase in diagnostic yield justifies the increase in costs. Patients and methods: We sequenced the exomes of eight individuals with sporadic syndromic ID and their parents. Results and discussion: 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. Keywords: exome, intellectual disability, next-generation sequencing