High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

• Published in: Human genetics 2015-09, Vol.134 (9), p.967-980
• Main Authors: Yavarna, Tarunashree, Al-Dewik, Nader, Al-Mureikhi, Mariam, Ali, Rehab, Al-Mesaifri, Fatma, Mahmoud, Laila, Shahbeck, Noora, Lakhani, Shenela, AlMulla, Mariam, Nawaz, Zafar, Vitazka, Patrik, Alkuraya, Fowzan S., Ben-Omran, Tawfeg
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Arabs - genetics; Biomedical and Life Sciences; Biomedicine; Child; Child development; Child, Preschool; Consanguinity; Cytogenetics; Developmental Disabilities - diagnosis; Developmental Disabilities - genetics; Epilepsy - genetics; Exome; Family medical history; Female; Gene Function; Genetic disorders; Genetic Testing; Genetics; Genomes; Genomics; Human Genetics; Humans; Infant; Intellectual disabilities; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Male; Metabolic Diseases; Microcephaly - genetics; Middle Aged; Molecular Medicine; Mutation; Original Investigation; Phenotype; Qatar; Sequence Analysis, DNA - methods; Young Adult
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-015-1575-0

Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60 %. Consanguinity and positive family history predicted a higher diagnostic yield. In 5 % (7/149) of cases, CES implicated novel candidate disease genes ( MANF , GJA9 , GLG1 , COL15A1 , SLC35F5 , MAGE4 , NEUROG1 ). CES uncovered two coexisting genetic disorders in 4 % (6/149) and actionable incidental findings in 2 % (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.