Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

Hum Genet. 2019 Jun;138(6):593-600. doi: 10.1007/s00439-019-02000-0.

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 ¹⁴

Affiliations

1 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
2 Institute of Human Genetics, University of Ulm, Ulm, Germany.
3 Department of Biotechnology, Balochistan University of Information Technology, Engineering, and Management Sciences, Quetta, Pakistan.
4 Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA.
5 Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.
6 Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan.
7 Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat, Pakistan.
8 Department of Computer Science and Bioinformatics, Khushal Khan Khattak University, Karak, Pakistan.
9 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
10 Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
11 Cologne Center for Genomics (CCG), Universitat zu Koln, Cologne, Germany.
12 Department of Genome Sciences, University of Washington, Seattle, USA.
13 Department of Pediatrics, University of Washington, Seattle, WA, USA.
14 Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA. sleal@bcm.edu.
# Contributed equally.

PMID: 30982135 DOI: 10.1007/s00439-019-02000-0

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.

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