Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families
| Autor: | Konstantinos Aliferis, David Neil Cooper, Stefania Gimelli, E. Kanavakis, Lorraine Gwanmesia, Sofia Kitsiou-Tzeli, Abdelaziz Sefiani, Frédérique Béna, Habiba Chaabouni Bouhamed, Helen Fryssira, Samia A. Temtamy, Stavroula Psoni, Nasir A. S. Al-Allawi, Hanan Hamamy, Georgios Stamoulis, Nadine Jalkh, André Mégarbané, Ebtesam M. Abdalla, Stylianos E. Antonarakis, Mari Nelis, Siham Chafai Elalaoui, Periklis Makrythanasis, Amira Masri, Siv Fokstuen, Lihadh Al-Gazali, Sana' Al Hait, Mariana Bustamante Eduardo, Michel Guipponi, Anne Vannier, Armand Bottani, Maha S. Zaki, Fatma Al-Jasmi, Federico Santoni, Mona Aglan, Elisavet Stathaki |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Adolescent Genes Recessive Consanguinity Biology DNA sequencing Young Adult 03 medical and health sciences Rare Diseases Genotype Genetics Humans Exome ddc:576.5 Child Genetics (clinical) Exome sequencing 030304 developmental biology 0303 health sciences 030305 genetics & heredity Infant Sequence Analysis DNA Disease gene identification Arabs Pedigree 3. Good health Child Preschool Female SNP array Comparative genomic hybridization |
| Zdroj: | Human Mutation, Vol. 35, No 10 (2014) pp. 1203-10 HUMAN MUTATION |
| ISSN: | 1059-7794 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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