title: Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.
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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: S
authors.initials: S
authors.lastname: Anazi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: S
authors.initials: S
authors.lastname: Maddirevula
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: E
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.lastname: Alsedairy
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: H E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.lastname: Patel
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: M
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authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: N
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authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: F
authors.initials: F
authors.lastname: Abdulwahab
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: N
authors.initials: N
authors.lastname: Ewida
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: H S
authors.initials: HS
authors.lastname: Alsaif
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: H
authors.initials: H
authors.lastname: Al Sharif
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: W
authors.initials: W
authors.lastname: Alamoudi
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Kentab
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: F A
authors.initials: FA
authors.lastname: Bashiri
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
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authors.initials: M
authors.lastname: Alnaser
authors.affiliation: Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
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authors.initials: AH
authors.lastname: AlWadei
authors.affiliation: Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: M
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authors.lastname: Alfadhel
authors.affiliation: Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: W
authors.initials: W
authors.lastname: Eyaid
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Hashem
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Al Asmari
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
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authors.initials: MM
authors.lastname: Saleh
authors.affiliation: Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
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authors.initials: A
authors.lastname: AlSaman
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: K A
authors.initials: KA
authors.lastname: Alhasan
authors.affiliation: Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
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authors.lastname: Alsughayir
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M
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authors.lastname: Al Shammari
authors.affiliation: Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
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authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Z N
authors.initials: ZN
authors.lastname: Al-Hassnan
authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Al-Husain
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.|National Research Center, Cairo, Egypt.
authors.forename: R
authors.initials: R
authors.lastname: Osama Khalil
authors.affiliation: National Research Center, Cairo, Egypt.
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authors.lastname: Abd El Meguid
authors.affiliation: Department of Pediatrics, Faculty of Medicine, The University of Jordan, Amman, Jordan.
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authors.affiliation: Clinical & Metabolic Genetics, Pediatrics, Hamad Medical Corporation, Doha, Qatar.
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authors.affiliation: Clinical & Metabolic Genetics, Pediatrics, Hamad Medical Corporation, Doha, Qatar.
authors.forename: T
authors.initials: T
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authors.affiliation: Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT, USA.
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authors.lastname: El Fishway
authors.affiliation: National Research Center, Cairo, Egypt.
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authors.initials: A
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authors.affiliation: Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT, USA.
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authors.initials: A
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authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
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authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: A M
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authors.affiliation: Department of Pediatrics, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
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authors.initials: MA
authors.lastname: Salih
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: N
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authors.lastname: Altassan
authors.affiliation: 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.
authors.forename: S T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: R
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authors.lastname: Shaheen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
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mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics; D005260:Female; D023281:Genomics; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D007621:Karyotyping / Q000379:methods; D008297:Male; D009154:Mutation; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult