1. Division of Biochemical Diseases; 2. Department of Pediatrics; 3. Treatable Intellectual Disability Endeavour in British Columbia (www.tidebc.org); 4. Centre for Molecular Medicine and Therapeutics; 5. Department of Medical Genetics; 6.Biochemical Genetics Laboratory; 7.Department of Pathology & Laboratory Medicine; B.C. Children’s Hospital, University of British Columbia, Vancouver, B.C. Canada; 8. Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO, U.S.A.
Introduction: Intellectual disability (ID) is a lifelong, debilitating condition affecting 2.5% of the population worldwide. Our TIDEX project aimed to identify novel (potentially treatable) ID genes employing the utility of the metabolic phenotype.
Methods: Criteria were applied to select patients for whole exome sequencing (WES): patient with unexplained, Mendelian ID plus metabolic abnormalities. WES was performed for trio’s with customized bio-informatics and subsequent validation.
Results: In 10 families meeting selection criteria, we discovered 7 new gene defects (various phases of functional validation), including carbonic anhydrase VA deficiency (siblings with hyperammonemia /-lactatemia), Rabosyn5 deficiency (early endosomal recycling defect in female with intractable epilepsy), acetyl-coA carboxylase 2 deficiency (in boy with biotin responsive phenotype), DSCAML1 deficiency (neuronal arborization defect in male with progressive white matter loss), NEU4 deficiency (sialidase deficiency in boy with neurodegenerative disease), as well as biotin responsive gene and neurotransmitter homeostasis genes. New phenotypes of known genes were detected in 2, including RMND1 defect in boy with kidney failure and encephalomyopathy.
Conclusions: Our success rate (>70%) emphasizes the advantages of the metabolic phenotype for gene discovery including: facilitation candidate gene hypothesis, validation causality identified variants, and targets for improved management / treatment with direct translation into patient care. This program will be expanded into ‘Omics2TreatID’ (www.omics2treatID) to study 70 families using a combined genomics-metabolomics approach.