title: High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.
abstract: 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.
authors.affiliation: Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O.BOX. 3050, Doha, Qatar.
authors.forename: Tarunashree
authors.initials: T
authors.lastname: Yavarna
authors.forename: Nader
authors.initials: N
authors.lastname: Al-Dewik
authors.forename: Mariam
authors.initials: M
authors.lastname: Al-Mureikhi
authors.forename: Rehab
authors.initials: R
authors.lastname: Ali
authors.forename: Fatma
authors.initials: F
authors.lastname: Al-Mesaifri
authors.forename: Laila
authors.initials: L
authors.lastname: Mahmoud
authors.forename: Noora
authors.initials: N
authors.lastname: Shahbeck
authors.forename: Shenela
authors.initials: S
authors.lastname: Lakhani
authors.forename: Mariam
authors.initials: M
authors.lastname: AlMulla
authors.forename: Zafar
authors.initials: Z
authors.lastname: Nawaz
authors.forename: Patrik
authors.initials: P
authors.lastname: Vitazka
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
mesh_terms: D000293:Adolescent; D000328:Adult; D018912:Arabs / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D059472:Exome; D005260:Female; D005820:Genetic Testing; D023281:Genomics; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D011780:Qatar; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult