| Affiliation: | 1. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland;2. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland;3. Estonian Genome Centre, University of Tartu, Tartu, Estonia;4. Department of Clinical Genetics, National Research Centre, Cairo, Egypt;5. Medical Genetics Unit, Saint Joseph University, Beirut, Lebanon;6. Institut Jer?me Lejeune, Paris, France;7. Pediatric Department, The University of Jordan, Amman, Jordan;8. Department of Medical Genetics, University of Athens, Athens, Greece;9. Department of Pathology, College of Medicine, University of Dohuk, Dohuk, Iraq;10. Department of Medical Genetics, Institut National d'Hygiène, Rabat, Morocco;11. Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohamed V Souissi, Rabat, Morocco;12. Genetics & IVF Department, The Farah Hospital, Amman, Jordan;13. Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al‐Ain, United Arab Emirates;14. Department of Pediatrics, Tawam Hospital, United Arab Emirates University, Al‐Ain, United Arab Emirates;15. Department of Human Genetics, Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia;16. Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt;17. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK;18. iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland |
| 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. |
