학술논문
Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families
Document Type
Academic Journal
Author
Makrythanasis, Periklis; Nelis, Mari; Santoni, Federico A.; Guipponi, Michel; Vannier, Anne; Béna, Frédérique; Gimelli, Stefania; Stathaki, Elisavet; Temtamy, Samia; Mégarbané, André; Masri, Amira; Aglan, Mona S.; Zaki, Maha S.; Bottani, Armand; Fokstuen, Siv; Gwanmesia, Lorraine; Aliferis, Konstantinos; Bustamante Eduardo, Mariana; Stamoulis, Georgios; Psoni, Stavroula; Kitsiou-Tzeli, Sofia; Fryssira, Helen; Kanavakis, Emmanouil; Al-Allawi, Nasir; Sefiani, Abdelaziz; Al Hait, Sanaʼ; Elalaoui, Siham C.; Jalkh, Nadine; Al-Gazali, Lihadh; Al-Jasmi, Fatma; Bouhamed, Habiba Chaabouni; Abdalla, Ebtesam; Cooper, David N.; Hamamy, Hanan; Antonarakis, Stylianos E.
Source
Human Mutation. Oct 01, 2014 35(10):1203-1210
Subject
Language
English
ISSN
1059-7794
Abstract
Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for 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.