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Human Genetics

, Volume 137, Issue 9, pp 735–752 | Cite as

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

  • Regie Lyn P. Santos-Cortez
  • Valeed Khan
  • Falak Sher Khan
  • Zaib-un-Nisa Mughal
  • Imen Chakchouk
  • Kwanghyuk Lee
  • Memoona Rasheed
  • Rifat Hamza
  • Anushree Acharya
  • Ehsan Ullah
  • Muhammad Arif Nadeem Saqib
  • Izoduwa Abbe
  • Ghazanfar Ali
  • Muhammad Jawad Hassan
  • Saadullah Khan
  • Zahid Azeem
  • Irfan Ullah
  • Michael J. Bamshad
  • Deborah A. Nickerson
  • Isabelle Schrauwen
  • Wasim Ahmad
  • Muhammad Ansar
  • Suzanne M. LealEmail author
Original Investigation

Abstract

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

Notes

Acknowledgements

We thank the families who participated in this study. We also thank the following who provided genotyping and sequencing services at the University of Washington Center for Mendelian Genomics (UW-CMG): Michael J. Bamshad1,2, Suzanne M. Leal3, and Deborah A. Nickerson1; Peter Anderson1, Marcus Annable1, Elizabeth E. Blue1, Kati J. Buckingham1, Imen Chakchouk3, Jennifer Chin1, Jessica X Chong1, Rodolfo Cornejo Jr.1, Colleen P. Davis1, Christopher Frazar1, Martha Horike-Pyne1, Gail P. Jarvik1, Eric Johanson1, Ashley N. Kang1, Tom Kolar1, Stephanie A. Krauter1, Colby T. Marvin1, Sean McGee1, Daniel J. McGoldrick1, Karynne Patterson1, Sam W. Phillips1, Jessica Pijoan1, Matthew A. Richardson1, Peggy D. Robertson1, Isabelle Schrauwen3, Krystal Slattery1, Kathryn M. Shively1, Joshua D. Smith1, Monica Tackett1, Alice E. Tattersall1, Marc Wegener1, Jeffrey M. Weiss1, Marsha M. Wheeler1, Qian Yi1, and Di Zhang3; Affiliations—1University of Washington; 2Seattle Children’s Hospital; 3Baylor College of Medicine. UW-CMG was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant HG006493 (to D. Nickerson, M. Bamshad and S. Leal). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by funds from the Higher Education Commission, Islamabad, Pakistan (to W. Ahmad).

Supplementary material

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Supplementary material 1 (DOCX 25 KB)
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Supplementary material 2 (PNG 573 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Regie Lyn P. Santos-Cortez
    • 1
    • 2
  • Valeed Khan
    • 3
  • Falak Sher Khan
    • 3
  • Zaib-un-Nisa Mughal
    • 3
  • Imen Chakchouk
    • 1
  • Kwanghyuk Lee
    • 1
  • Memoona Rasheed
    • 3
  • Rifat Hamza
    • 3
  • Anushree Acharya
    • 1
  • Ehsan Ullah
    • 3
  • Muhammad Arif Nadeem Saqib
    • 3
    • 4
  • Izoduwa Abbe
    • 1
  • Ghazanfar Ali
    • 5
  • Muhammad Jawad Hassan
    • 6
  • Saadullah Khan
    • 7
  • Zahid Azeem
    • 8
  • Irfan Ullah
    • 3
  • Michael J. Bamshad
    • 9
    • 10
  • Deborah A. Nickerson
    • 9
  • Isabelle Schrauwen
    • 1
  • Wasim Ahmad
    • 3
  • Muhammad Ansar
    • 3
  • Suzanne M. Leal
    • 1
    Email author
  1. 1.Department of Molecular and Human GeneticsCenter for Statistical Genetics, Baylor College of MedicineHoustonUSA
  2. 2.Department of OtolaryngologyUniversity of Colorado School of MedicineAuroraUSA
  3. 3.Department of Biochemistry, Faculty of Biological SciencesQuaid-i-Azam UniversityIslamabadPakistan
  4. 4.Pakistan Health Research CouncilIslamabadPakistan
  5. 5.Department of BiotechnologyUniversity of Azad Jammu and KashmirMuzaffarabadPakistan
  6. 6.Department of Healthcare BiotechnologyAtta-ur-Rahman School of Applied Biosciences, National University of Sciences and TechnologyIslamabadPakistan
  7. 7.Department of Biotechnology and Genetic EngineeringKohat University of Science and TechnologyKohatPakistan
  8. 8.Department of BiochemistryAzad Jammu and Kashmir Medical CollegeMuzaffarabadPakistan
  9. 9.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  10. 10.Department of PediatricsUniversity of WashingtonSeattleUSA

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