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Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

  • Irfan Ullah
  • Naseebullah Kakar
  • Isabelle Schrauwen
  • Shabir Hussain
  • Imen Chakchouk
  • Khurram Liaqat
  • Anushree Acharya
  • Naveed Wasif
  • Regie Lyn P. Santos-Cortez
  • Saadullah Khan
  • Abdul Aziz
  • Kwanghyuk Lee
  • Julien Couthouis
  • Denise Horn
  • Bjørt K. Kragesteen
  • Malte Spielmann
  • Holger Thiele
  • Deborah A. Nickerson
  • Michael J. Bamshad
  • Aaron D. Gitler
  • Jamil Ahmad
  • Muhammad Ansar
  • Guntram Borck
  • Wasim Ahmad
  • Suzanne M. LealEmail author
Original Investigation
  • 76 Downloads

Abstract

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

Notes

Acknowledgements

The authors would like to thank the family members who participated in this study. This work was supported by funds from the Higher Education Commission (HEC), Islamabad, Pakistan (to WA). A Georg Forster fellowship was provided by the Alexander von Humboldt Foundation (to NW). Genotyping and exome sequencing for family BD204 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant UM1 HG006493 (to DAN, MJB, and SML) and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Web Resources: ANNOVAR, http://annovar.openbioinformatics.org/. Burrows-Wheeler Aligner (BWA), http://bio-bwa.sourceforge.net/. Combined Annotation Dependent Depletion (CADD), http://cadd.gs.washington.edu/. Gene Expression Ommibus (GEO), https://www.ncbi.nlm.nih.gov/geo/. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org/. Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/gatk/. ENCODE project, https://www.encodeproject.org/. HomozygosityMapper, http://www.homozygositymapper.org/. International Mouse Phenotyping Consortium (IMPC), http://www.mousephenotype.org. Varbank pipeline v.2.3, https://varbank.ccg.uni-koeln.de/.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Supplementary material 1 (DOCX 2869 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Irfan Ullah
    • 1
  • Naseebullah Kakar
    • 2
    • 3
  • Isabelle Schrauwen
    • 4
  • Shabir Hussain
    • 1
    • 4
  • Imen Chakchouk
    • 4
  • Khurram Liaqat
    • 4
    • 5
  • Anushree Acharya
    • 4
  • Naveed Wasif
    • 2
    • 6
  • Regie Lyn P. Santos-Cortez
    • 4
  • Saadullah Khan
    • 7
  • Abdul Aziz
    • 1
    • 8
  • Kwanghyuk Lee
    • 4
  • Julien Couthouis
    • 9
  • Denise Horn
    • 10
  • Bjørt K. Kragesteen
    • 10
  • Malte Spielmann
    • 10
  • Holger Thiele
    • 11
  • Deborah A. Nickerson
    • 12
  • Michael J. Bamshad
    • 12
    • 13
  • Aaron D. Gitler
    • 9
  • Jamil Ahmad
    • 3
  • Muhammad Ansar
    • 1
  • Guntram Borck
    • 2
  • Wasim Ahmad
    • 1
  • Suzanne M. Leal
    • 4
    Email author
  1. 1.Department of Biochemistry, Faculty of Biological SciencesQuaid-i-Azam UniversityIslamabadPakistan
  2. 2.Institute of Human GeneticsUniversity of UlmUlmGermany
  3. 3.Department of BiotechnologyBalochistan University of Information Technology, Engineering, and Management SciencesQuettaPakistan
  4. 4.Department of Molecular and Human Genetics, Center for Statistical GeneticsBaylor College of MedicineHoustonUSA
  5. 5.Department of Biotechnology, Faculty of Biological SciencesQuaid-i-Azam University IslamabadIslamabadPakistan
  6. 6.Institute of Molecular Biology and Biotechnology (IMBB)The University of LahoreLahorePakistan
  7. 7.Department of Biotechnology and Genetic EngineeringKohat University of Science and TechnologyKohatPakistan
  8. 8.Department of Computer Science and BioinformaticsKhushal Khan Khattak UniversityKarakPakistan
  9. 9.Department of GeneticsStanford University School of MedicineStanfordUSA
  10. 10.Institute for Medical Genetics and Human GeneticsCharité Universitätsmedizin BerlinBerlinGermany
  11. 11.Cologne Center for Genomics (CCG)Universitat zu KolnCologneGermany
  12. 12.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  13. 13.Department of PediatricsUniversity of WashingtonSeattleUSA

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