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

• Published in: Human mutation Vol. 35; no. 10; pp. 1203 - 1210
• Main Authors: 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, Sana', Elalaoui, Siham C., Jalkh, Nadine, Al-Gazali, Lihadh, Al-Jasmi, Fatma, Bouhamed, Habiba Chaabouni, Abdalla, Ebtesam, Cooper, David N., Hamamy, Hanan, Antonarakis, Stylianos E.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2014; Hindawi Limited
• Subjects: Adolescent; Adult; Arabs; Child; Child, Preschool; Consanguinity; Exome; exome sequencing; Female; Genes, Recessive - genetics; Genetic disorders; Genetic testing; Genotype & phenotype; high-throughput sequencing; homozygosity mapping; Humans; Infant; Male; Mutation; Pedigree; Rare Diseases - diagnosis; Rare Diseases - genetics; Sequence Analysis, DNA; Young Adult; exome sequencing; consanguinity; homozygosity mapping; high-throughput sequencing
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22617

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.