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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References
Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101. https://doi.org/10.1038/ng786
Al-Qattan MM (2012) A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. Clin Genet 82:502–504. https://doi.org/10.1111/j.1399-0004.2012.01866.x
Barham G, Clarke NMP (2008) Genetic regulation of embryological limb development with relation to congenital limb deformity in humans. J Child Orthop 2:1–9. https://doi.org/10.1007/s11832-008-0076-2
Biesecker LG (2011) Polydactyly: how many disorders and how many genes? 2010 update. Dev Dyn 240:931–942. https://doi.org/10.1002/dvdy.22609
Cardoso C, Boys A, Parrini E et al (2009) Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology 72:784–792. https://doi.org/10.1212/01.wnl.0000336339.08878.2d
Castilla E, Paz J, Mutchinick O et al (1973) Polydactyly: a genetic study in South America. Am J Hum Genet 25:405–412
Duboc V, Logan MP (2009) Building limb morphology through integration of signalling modules. Curr Opin Genet Dev 19:497–503. https://doi.org/10.1016/j.gde.2009.07.002
Edgar R, Domrachev M, Lash AE (2002) Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210
ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74. https://doi.org/10.1038/nature11247
Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11:331–344. https://doi.org/10.1038/nrg2774
Grzeschik K-H (2002) Human limb malformations; an approach to the molecular basis of development. Int J Dev Biol 46:983–991
Hug N, Longman D, Cáceres JF (2016) Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res 44:1483–1495. https://doi.org/10.1093/nar/gkw010
Kalsoom U-, Klopocki E, Wasif N et al (2013) Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A. J Med Genet 50:47–53. https://doi.org/10.1136/jmedgenet-2012-101219
Kircher M, Witten DM, Jain P et al (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. https://doi.org/10.1038/ng.2892
Koscielny G, Yaikhom G, Iyer V et al (2014) The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data. Nucleic Acids Res 42:D802–D809. https://doi.org/10.1093/nar/gkt977
Langmead B, Wilks C, Antonescu V, Charles R (2018) Scaling read aligners to hundreds of threads on general-purpose processors. Bioinformatics. https://doi.org/10.1093/bioinformatics/bty648
Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. https://doi.org/10.1093/bioinformatics/btp324
Li H, Handsaker B, Wysoker A et al (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. https://doi.org/10.1093/bioinformatics/btp352
Loomis CA, Kimmel RA, Tong CX et al (1998) Analysis of the genetic pathway leading to formation of ectopic apical ectodermal ridges in mouse Engrailed-1 mutant limbs. Development 125:1137–1148
Malik S, Ullah S, Afzal M et al (2014) Clinical and descriptive genetic study of polydactyly: a Pakistani experience of 313 cases. Clin Genet 85:482–486. https://doi.org/10.1111/cge.12217
Martin P (1990) Tissue patterning in the developing mouse limb. Tissue patterning in the developing mouse limb. Int J Dev Biol 34:323–336
McKenna A, Hanna M, Banks E et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. https://doi.org/10.1101/gr.107524.110
Ng SB, Buckingham KJ, Lee C et al (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42:30–35. https://doi.org/10.1038/ng.499
O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266. https://doi.org/10.1086/301904
Palencia-Campos A, Ullah A, Nevado J et al (2017) GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Hum Mol Genet 26:4556–4571. https://doi.org/10.1093/hmg/ddx335
Parla JS, Iossifov I, Grabill I et al (2011) A comparative analysis of exome capture. Genome Biol 12:R97. https://doi.org/10.1186/gb-2011-12-9-r97
Pompe van Meerdervoort HF (1976) Congenital musculoskeletal malformation in South African Blacks: a study of incidence. S Afr Med J 50:1853–1855
Radhakrishna U, Bornholdt D, Scott HS et al (1999) The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 65:645–655. https://doi.org/10.1086/302557
Schrauwen I, Giese AP, Aziz A et al FAM92A underlies nonsyndromic postaxial polydactyly in humans and an abnormal limb and digit skeletal phenotype in mice. J Bone Miner Res. https://doi.org/10.1002/jbmr.3594
Schwabe GC, Mundlos S (2004) Genetics of congenital hand anomalies. Handchir Mikrochir Plast Chir 36:85–97. https://doi.org/10.1055/s-2004-817884
Seelow D, Schuelke M (2012) HomozygosityMapper2012—bridging the gap between homozygosity mapping and deep sequencing. Nucleic Acids Res 40:W516–W520. https://doi.org/10.1093/nar/gks487
Spielmann M, Kakar N, Tayebi N et al (2016) Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res 26:183–191. https://doi.org/10.1101/gr.199430.115
Umair M, Shah K, Alhaddad B et al (2017) Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb. Eur J Hum Genet 25:960–965. https://doi.org/10.1038/ejhg.2017.83
Umm-e-Kalsoom, Basit S, Kamran-ul-Hassan Naqvi S et al (2012) Genetic mapping of an autosomal recessive postaxial polydactyly type A to chromosome 13q13.3-q21.2 and screening of the candidate genes. Hum Genet 131:415–422. https://doi.org/10.1007/s00439-011-1085-7
Verma PK, El-Harouni AA (2015) Review of literature: genes related to postaxial polydactyly. Front Pediatr 3:8. https://doi.org/10.3389/fped.2015.00008
Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164. https://doi.org/10.1093/nar/gkq603
Watson BT, Hennrikus WL (1997) Postaxial type-B polydactyly. Prevalence and treatment. J Bone Jt Surg Am 79:65–68
Yang Y, Niswander L (1995) Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Cell 80:939–947
Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394. https://doi.org/10.1089/1066527041410418
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/.
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Ullah, I., Kakar, N., Schrauwen, I. et al. Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly. Hum Genet 138, 593–600 (2019). https://doi.org/10.1007/s00439-019-02000-0
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DOI: https://doi.org/10.1007/s00439-019-02000-0