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

Periklis Makrythanasis, Mari Nelis, Federico A. Santoni, Michel Guipponi, Anne Vannier, Frédérique Béna, Stefania Gimelli, Elisavet Stathaki, Samia Temtamy, André Mégarbané, Amira Masri, Mona S. Aglan, Maha S. Zaki, Armand Bottani, Siv Fokstuen, Lorraine Gwanmesia, Konstantinos Aliferis, Mariana Bustamante Eduardo, Georgios Stamoulis, Stavroula Psoni, Sofia Kitsiou‐Tzeli, Helen Fryssira, Emmanouil Kanavakis, Nasir Al‐Allawi, Abdelaziz Sefiani, Sana' Al Hait, Siham C. Elalaoui, Nadine Jalkh, Lihadh Al‐Gazali, Fatma Al‐Jasmi, Habiba Chaabouni Bouhamed, Ebtesam Abdalla, David N. Cooper, Hanan Hamamy, Stylianos E. Antonarakis

Rare, atypical and undiagnosed autosomal recessive (AR) 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 AR 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 AR 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 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 aCGH 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. This article is protected by copyright. All rights reserved.