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Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Molecular Psychiatry volume 22, pages 615–624 (2017)Cite this article

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Abstract

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

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Acknowledgements

We thank the study families for their enthusiastic participation. This work was supported by KACST Grant 13-BIO1113-20 (FSA) and the Saudi Human Genome Project. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).

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Author notes

  1. S Anazi, S Maddirevula and E Faqeih: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    S Anazi, S Maddirevula, H Alsedairy, F Alzahrani, H E Shamseldin, N Patel, M Hashem, N Ibrahim, F Abdulwahab, N Ewida, H S Alsaif, H Al sharif, W Alamoudi, Z N Al-Hassnan, A M Alazami, N Altassan, M Abouelhoda, S M Wakil, D Monies, R Shaheen & F S Alkuraya

  2. Department of Pediatric Subspecialties, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia

    E Faqeih, A Al Asmari & M M Saleh

  3. Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

    A Kentab, F A Bashiri, M Alnaser, K A Alhasan, M Al Shammari, M Al-Husain & M A Salih

  4. Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia

    A H AlWadei, A AlSaman & A Mahmoud

  5. Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    M Alfadhel & W Eyaid

  6. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

    A Hashem

  7. Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    M Alsughayir

  8. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    R Osama Khalil & M State

  9. National Research Center, Cairo, Egypt

    R Osama Khalil, N Abd El.Meguid & A Hashish

  10. Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT, USA

    P El.Fishway & A Ercan Sencicek

  11. Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia

    S T Arold

  12. Department of Pediatrics, Faculty of Medicine, The University of Jordan, Amman, Jordan

    A Masri

  13. Clinical & Metabolic Genetics, Pediatrics, Hamad Medical Corporation, Doha, Qatar

    R Ali & T Ben-Omran

  14. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    F S Alkuraya

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  1. S Anazi
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  2. S Maddirevula
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  38. A Ercan Sencicek
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  39. M State
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  40. A M Alazami
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  41. M A Salih
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  42. N Altassan
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  43. S T Arold
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  44. M Abouelhoda
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  45. S M Wakil
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  46. D Monies
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  47. R Shaheen
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  48. F S Alkuraya
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Corresponding authors

Correspondence to R Shaheen or F S Alkuraya.

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Anazi, S., Maddirevula, S., Faqeih, E. et al. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry 22, 615–624 (2017). https://doi.org/10.1038/mp.2016.113

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