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Human Genetics

, Volume 136, Issue 11–12, pp 1419–1429 | Cite as

Expanding the genetic heterogeneity of intellectual disability

  • Shams Anazi
  • Sateesh Maddirevula
  • Vincenzo Salpietro
  • Yasmine T. Asi
  • Saud Alsahli
  • Amal Alhashem
  • Hanan E. Shamseldin
  • Fatema AlZahrani
  • Nisha Patel
  • Niema Ibrahim
  • Firdous M. Abdulwahab
  • Mais Hashem
  • Nadia Alhashmi
  • Fathiya Al Murshedi
  • Adila Al Kindy
  • Ahmad Alshaer
  • Ahmed Rumayyan
  • Saeed Al Tala
  • Wesam Kurdi
  • Abdulaziz Alsaman
  • Ali Alasmari
  • Selina Banu
  • Tipu Sultan
  • Mohammed M. Saleh
  • Hisham Alkuraya
  • Mustafa A. Salih
  • Hesham Aldhalaan
  • Tawfeg Ben-Omran
  • Fatima Al Musafri
  • Rehab Ali
  • Jehan Suleiman
  • Brahim Tabarki
  • Ayman W. El-Hattab
  • Caleb Bupp
  • Majid Alfadhel
  • Nada Al Tassan
  • Dorota Monies
  • Stefan T. Arold
  • Mohamed Abouelhoda
  • Tammaryn Lashley
  • Henry Houlden
  • Eissa Faqeih
  • Fowzan S. AlkurayaEmail author
Original Investigation

Abstract

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease–gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

Notes

Acknowledgements

We thank the study families for their enthusiastic participation. This work was supported in part by King Salman Center for Disability Research (FSA). We acknowledge the support of the Saudi Human Genome Program and the Sequencing and Genotyping Core Facilities at KFSRHC. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).

Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest.

Supplementary material

439_2017_1843_MOESM1_ESM.pdf (165 kb)
Figure S1. A) Clinical features of patient with GTF3C3-related ID showing facial asymmetry, bilateral temporal narrowing, epicanthal folds, upslanting palpebral fissures, bulbous nose, and full cheeks. (C) Chromatogram showing skipping of exon10 and partial part of exon11 (PDF 164 kb)
439_2017_1843_MOESM2_ESM.xlsx (23 kb)
Supplementary material 2 (XLSX 23 kb)
439_2017_1843_MOESM3_ESM.docx (53 kb)
Supplementary material 3 (DOCX 54 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Shams Anazi
    • 1
  • Sateesh Maddirevula
    • 1
  • Vincenzo Salpietro
    • 21
  • Yasmine T. Asi
    • 2
  • Saud Alsahli
    • 1
  • Amal Alhashem
    • 3
  • Hanan E. Shamseldin
    • 1
  • Fatema AlZahrani
    • 1
  • Nisha Patel
    • 1
  • Niema Ibrahim
    • 1
  • Firdous M. Abdulwahab
    • 1
  • Mais Hashem
    • 1
  • Nadia Alhashmi
    • 4
  • Fathiya Al Murshedi
    • 4
  • Adila Al Kindy
    • 4
  • Ahmad Alshaer
    • 11
  • Ahmed Rumayyan
    • 5
    • 6
  • Saeed Al Tala
    • 7
  • Wesam Kurdi
    • 8
  • Abdulaziz Alsaman
    • 16
  • Ali Alasmari
    • 16
  • Selina Banu
    • 22
  • Tipu Sultan
    • 23
  • Mohammed M. Saleh
    • 16
  • Hisham Alkuraya
    • 9
  • Mustafa A. Salih
    • 10
  • Hesham Aldhalaan
    • 11
  • Tawfeg Ben-Omran
    • 12
  • Fatima Al Musafri
    • 12
  • Rehab Ali
    • 12
  • Jehan Suleiman
    • 13
  • Brahim Tabarki
    • 3
  • Ayman W. El-Hattab
    • 14
  • Caleb Bupp
    • 17
  • Majid Alfadhel
    • 18
  • Nada Al Tassan
    • 1
    • 15
  • Dorota Monies
    • 1
    • 15
  • Stefan T. Arold
    • 19
  • Mohamed Abouelhoda
    • 1
    • 15
  • Tammaryn Lashley
    • 2
  • Henry Houlden
    • 21
  • Eissa Faqeih
    • 16
  • Fowzan S. Alkuraya
    • 1
    • 3
    • 15
    • 20
    • 17
    Email author
  1. 1.Department of GeneticsKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  2. 2.Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of NeurologyUniversity College LondonLondonUK
  3. 3.Department of PediatricsPrince Sultan Military Medical CityRiyadhSaudi Arabia
  4. 4.Department of Genetics, College of MedicineSultan Qaboos UniversityMuscatSultanate of Oman
  5. 5.King Saud bin Abdulaziz University for Health SciencesRiyadhSaudi Arabia
  6. 6.Neurology Division, Department of PediatricsKing Abdulaziz Medical CityRiyadhSaudi Arabia
  7. 7.Department of Pediatrics and Genetic UnitArmed Forces HospitalKhamis MushaytSaudi Arabia
  8. 8.Department of Obstetrics and GynecologyKing Faisal Specialist HospitalRiyadhSaudi Arabia
  9. 9.Department of OphthalmologySpecialized Medical Center HospitalRiyadhSaudi Arabia
  10. 10.Division of Pediatric Neurology, Department of Pediatrics, King Khalid University Hospital and College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  11. 11.Pediatric NeurologyKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  12. 12.Clinical and Metabolic Genetics, Department of PediatricsHamad Medical CorporationDohaQatar
  13. 13.Division of Neurology, Department of PediatricsTawam HospitalAl AinUnited Arab Emirates
  14. 14.Division of Clinical Genetics and Metabolic Disorders, Department of PediatricsTawam HospitalAl-AinUnited Arab Emirates
  15. 15.Saudi Human Genome ProgramKing Abdulaziz City for Science and TechnologyRiyadhSaudi Arabia
  16. 16.Department of Pediatric Subspecialties, Children’s HospitalKing Fahad Medical CityRiyadhSaudi Arabia
  17. 17.Spectrum Health GeneticsGrand RapidsUSA
  18. 18.Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health SciencesKing Abdulaziz Medical CityRiyadhSaudi Arabia
  19. 19.Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC)King Abdullah University of Science and Technology (KAUST)ThuwalSaudi Arabia
  20. 20.Division of Biological and Environmental Sciences and Engineering (BESE)King Abdullah University of Science and Technology (KAUST)ThuwalSaudi Arabia
  21. 21.Department of Molecular NeuroscienceUCL Institute of NeurologyLondonUK
  22. 22.Department of Pediatric NeurologyICH and SSF Hospital MirpurDhakaBangladesh
  23. 23.Department of Pediatric NeurologyInstitute of Child Health and The Children’s Hospital LahoreLahorePakistan

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