Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly
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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.
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/.
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Conflict of interest
The authors declare that they have no competing interests.
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