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Human Genetics

, Volume 134, Issue 9, pp 967–980 | Cite as

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

  • Tarunashree Yavarna
  • Nader Al-Dewik
  • Mariam Al-Mureikhi
  • Rehab Ali
  • Fatma Al-Mesaifri
  • Laila Mahmoud
  • Noora Shahbeck
  • Shenela Lakhani
  • Mariam AlMulla
  • Zafar Nawaz
  • Patrik Vitazka
  • Fowzan S. AlkurayaEmail author
  • Tawfeg Ben-OmranEmail author
Original Investigation

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.

Keywords

Intellectual Disability Diagnostic Yield Pathogenic Variant Neurocognitive Disorder High Diagnostic Yield 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank all families described in this paper and the healthcare providers who were involved in their care. We would also like to thank Mr. Patricio Santos Ayroso for his administrative support.

Supplementary material

439_2015_1575_MOESM1_ESM.pdf (215 kb)
Supplementary material 1 (PDF 214 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Tarunashree Yavarna
    • 1
  • Nader Al-Dewik
    • 1
  • Mariam Al-Mureikhi
    • 1
  • Rehab Ali
    • 1
  • Fatma Al-Mesaifri
    • 1
  • Laila Mahmoud
    • 1
  • Noora Shahbeck
    • 1
  • Shenela Lakhani
    • 1
  • Mariam AlMulla
    • 1
  • Zafar Nawaz
    • 2
  • Patrik Vitazka
    • 3
  • Fowzan S. Alkuraya
    • 4
    • 5
    Email author
  • Tawfeg Ben-Omran
    • 1
    • 6
    Email author
  1. 1.Clinical and Metabolic Genetics, Department of PediatricsHamad Medical CorporationDohaQatar
  2. 2.Cytogenetics and Molecular Cytogenetics, Department of Pathology and Laboratory MedicineHamad Medical CorporationDohaQatar
  3. 3.GeneDxGaithersburgUSA
  4. 4.Developmental Genetics Unit, Department of Genetics, Research CenterKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  5. 5.Department of Anatomy and Cell Biology, College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
  6. 6.Weill Cornell Medical CollegeAl-RayyanQatar

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