{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:26:14Z","timestamp":1783081574051,"version":"3.54.6"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maternal and Child Health Hospital of Hubei Province","award":["2021SFYZ001"],"award-info":[{"award-number":["2021SFYZ001"]}]},{"name":"Maternal and Child Health Hospital of Hubei Province","award":["81570348"],"award-info":[{"award-number":["81570348"]}]},{"name":"National Natural Science Foundation of China","award":["2021SFYZ001"],"award-info":[{"award-number":["2021SFYZ001"]}]},{"name":"National Natural Science Foundation of China","award":["81570348"],"award-info":[{"award-number":["81570348"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and\/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found by fetal ultrasonography. To better evaluate fetal prognosis, SNP array analysis and trio whole-exome sequencing (trio-WES) were performed to identify the underlying etiology. Although SNP array analysis revealed no abnormality, trio-WES identified compound heterozygous splice site variants in KIAA0825, c.-1-2A&gt;T and c.2247-2A&gt;G in intron 2 and intron 12, respectively. These two splice site variants were absent in control databases and were predicted to influence splicing by in silico analysis. To confirm the potential pathogenicity of the variants, in vitro splicing assays using minigene and RNA from peripheral leukocytes of the heterozygous parents were conducted. Minigene and RT-PCR assays demonstrated that the c.-1-2A&gt;T variant led to the loss of the initiation codon, and the c.2247-2A&gt;G variant mainly resulted in exon 13 skipping. Prenatal WES and subsequent functional studies are important approaches for defining the genetic etiology of fetuses with PAPA and are also essential for accurate genetic counseling and decision making. Taken together, this study expands the spectrum of KIAA0825 variations in PAPA patients and increases the knowledge of the molecular consequences of KIAA0825 splice site variants.<\/jats:p>","DOI":"10.3390\/genes13071230","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T21:57:53Z","timestamp":1657576673000},"page":"1230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Prenatal Detection of Novel Compound Heterozygous Splice Site Variants of the KIAA0825 Gene in a Fetus with Postaxial Polydactyly Type A"],"prefix":"10.3390","volume":"13","author":[{"given":"Yanyi","family":"Yao","sequence":"first","affiliation":[{"name":"Medical Genetic Center, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2727-2722","authenticated-orcid":false,"given":"Shan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-5834","authenticated-orcid":false,"given":"Feng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3389\/fped.2015.00008","article-title":"Review of literature: Genes related to postaxial polydactyly","volume":"3","author":"Verma","year":"2015","journal-title":"Front. Pediatr."},{"key":"ref_2","first-page":"708","article-title":"Epidemiological analysis of polydactylies in Chinese perinatals","volume":"35","author":"Zhou","year":"2004","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1016\/j.ygeno.2020.03.006","article-title":"Identification of a novel biallelic missense variant in the KIAA0825 underlies postaxial polydactyly type A","volume":"112","author":"Hayat","year":"2020","journal-title":"Genomics"},{"key":"ref_4","first-page":"931","article-title":"Polydactyly: How many disorders and how many genes? 2010 update","volume":"2011","author":"Biesecker","year":"2010","journal-title":"Dev. Dyn."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/cge.12217","article-title":"Clinical and descriptive genetic study of polydactyly: A Pakistani experience of 313 cases","volume":"85","author":"Malik","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1399-0004.2012.01866.x","article-title":"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","volume":"82","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1136\/jmedgenet-2012-101219","article-title":"Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A","volume":"50","author":"Kalsoom","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/ejhg.2017.83","article-title":"Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb","volume":"25","author":"Umair","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00439-019-02000-0","article-title":"Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly","volume":"138","author":"Ullah","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1093\/hmg\/ddx335","article-title":"GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome","volume":"26","author":"Ullah","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/jbmr.3594","article-title":"FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice","volume":"34","author":"Schrauwen","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"447","DOI":"10.3389\/fgene.2018.00447","article-title":"Clinical Genetics of Polydactyly: An Updated Review","volume":"9","author":"Umair","year":"2018","journal-title":"Front. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1159\/000512062","article-title":"A Frameshift Variant in KIAA0825 Causes Postaxial Polydactyly","volume":"12","author":"Bilal","year":"2021","journal-title":"Mol. Syndr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"635703","DOI":"10.3389\/fped.2021.635703","article-title":"Detection of Disease-Causing SNVs\/Indels and CNVs in Single Test Based on Whole Exome Sequencing: A Retrospective Case Study in Epileptic Encephalopathies","volume":"9","author":"Sun","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nmeth.3484","article-title":"Phenolyzer: Phenotype-based prioritization of candidate genes for human diseases","volume":"12","author":"Yang","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12696","DOI":"10.1038\/s41598-019-48990-9","article-title":"Determination of the pathogenicity of known COL4A5 intronic variants by in vitro splicing assay","volume":"9","author":"Horinouchi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41436-019-0731-7","article-title":"The use of fetal exome sequencing in prenatal diagnosis: A points to consider document of the American College of Medical Genetics and Genomics (ACMG)","volume":"22","author":"Monaghan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S0140-6736(18)32042-7","article-title":"Whole-exome sequencing in the evaluation of fetal structural anomalies: A prospective cohort study","volume":"393","author":"Petrovski","year":"2019","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0140-6736(18)31940-8","article-title":"Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): A cohort study","volume":"393","author":"Lord","year":"2019","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1111\/1471-0528.16616","article-title":"Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64 [February] 2021","volume":"128","author":"Mone","year":"2021","journal-title":"BJOG"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium","year":"2012","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D802","DOI":"10.1093\/nar\/gkt977","article-title":"The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data","volume":"42","author":"Koscielny","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/humu.23626","article-title":"Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion","volume":"39","author":"Pesaran","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1101\/gr.226050.117","article-title":"Discovery of noncanonical translation initiation sites through mass spectrometric analysis of protein N termini","volume":"28","author":"Na","year":"2018","journal-title":"Genome Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D845","DOI":"10.1093\/nar\/gkt1085","article-title":"TISdb: A database for alternative translation initiation in mammalian cells","volume":"42","author":"Wan","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.tig.2020.11.002","article-title":"To NMD or Not To NMD: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases","volume":"37","author":"Supek","year":"2021","journal-title":"Trends Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.gim.2021.09.001","article-title":"Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants","volume":"24","author":"Bournazos","year":"2022","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1002\/cphg.98","article-title":"Clinical Interpretation of Sequence Variants","volume":"106","author":"Zhang","year":"2020","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1230\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:48:17Z","timestamp":1760140097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["genes13071230"],"URL":"https:\/\/doi.org\/10.3390\/genes13071230","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]}}}