Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families

Rare atypical, and undiagnosed autosomal cessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic asste eices. employed netic tests fail to establish a diagntoseisin m g exiiine sequencing to identify t h an e u nderlving molecular defects in patients with in unresolved o e but pu.atively autosomal-recessive disorders consanguineous families and postulated that the pathogenic variants would families within h ornozygous regions. Fifty consanguineous t es participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosonial-recessiv e inheritance, but with no definitive molecular diagnosis. I)NA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exonie sequencing and array CGH (comparative ve genotriic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variant: were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array UGH and 17 by exoine sequencing), accounting the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes. (C) 2014 2014 Willey Periodicals