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Mol Psychiatry. 2017 Apr;22(4):615-624. doi: 10.1038/mp.2016.113. Epub 2016 Jul 19.

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

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
3
Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
4
Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
5
Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
6
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
7
Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
8
Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
9
National Research Center, Cairo, Egypt.
10
Department of Pediatrics, Faculty of Medicine, The University of Jordan, Amman, Jordan.
11
Clinical & Metabolic Genetics, Pediatrics, Hamad Medical Corporation, Doha, Qatar.
12
Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT, USA.
13
King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal, Saudi Arabia.
14
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

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.

PMID:
27431290
DOI:
10.1038/mp.2016.113
[Indexed for MEDLINE]

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