{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:49:55Z","timestamp":1753861795881,"version":"3.41.2"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100014895","name":"Southwest Medical University","doi-asserted-by":"publisher","award":["00040164","202310632061"],"award-info":[{"award-number":["00040164","202310632061"]}],"id":[{"id":"10.13039\/501100014895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>BDA4 and BDD are rare autosomal dominant conditions characterized by distinct hand\/foot malformations, including middle phalangeal shortening in the second and fifth digits and short, broad thumb terminal phalanges. While variations in <jats:italic>BMPR1B<\/jats:italic> have been implicated in the pathogenesis of BDA1 and BDA2, the genetic basis underlying BDA4 and BDD remains unclear. Clinical and radiographic phenotyping were performed to assess and diagnose the affected pedigree. Whole\u2010exome sequencing and Sanger sequencing were employed to identify and validate the genetic variation. Bioinformatics analyses were conducted to evaluate the potential pathogenicity of the variant. Functional validation was carried out by assessing SMAD4 localization in BMP4\u2010stimulated 293T transfectants. We present the first report of a rare Chinese Han pedigree exhibiting two distinct phenotypes: isolated BDA4 and incomplete BDA4 overlapping BDD, which were observed across two branches. All affected individuals harbored a novel heterozygous c.1024A&gt;G (p.K342E) variant in <jats:italic>BMPR1B<\/jats:italic>, with bioinformatics analyses suggesting its pathogenic potential. Structural analyses indicated a conformational change within the kinase domain. Functional assays revealed a marked reduction in nuclear SMAD4 accumulation in transfectants expressing the mutant BMPR1B compared to the wild\u2010type counterpart. This study provides the first evidence implicating <jats:italic>BMPR1B<\/jats:italic> as a pathogenic gene for both isolated BDA4 and incomplete BDA4 with BDD overlap. The <jats:italic>BMPR1B<\/jats:italic> c.1024A&gt;G (p.K342E) variant disrupts kinase activity and impairs SMAD1\/5\/8 phosphorylation, which in turn suppresses downstream IHH expression and interferes with BMP\u2010mediated skeletal patterning. We propose that the variant, in combination with genetic background and environmental factors, leads to the observed variable expressivity in this pedigree. Our findings expand the mutational spectrum of brachydactyly and underscore <jats:italic>BMPR1B<\/jats:italic> as a candidate gene for further investigation in brachydactyly pathogenesis.<\/jats:p>","DOI":"10.1002\/ajmg.a.64060","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T16:53:09Z","timestamp":1742748789000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Heterozygous <scp>c.1024A&gt;G<\/scp> Variant in <i>BMPR1B<\/i> Causes Either Isolated Brachydactyly Type <scp>A4<\/scp> With Variable Expressivity or Incomplete Type <scp>A4<\/scp> Overlapping Type D in a Chinese Han Pedigree"],"prefix":"10.1002","volume":"197","author":[{"given":"Xinyi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Imaging Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runji","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunping","family":"Shang","sequence":"additional","affiliation":[{"name":"Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songhua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences Southwest Medical University  Luzhou China"},{"name":"Laboratory of Xinjiang Endemic and Ethnic Diseases Shihezi University, Ministry of Education  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6207-1547","authenticated-orcid":false,"given":"Mingyi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences Southwest Medical University  Luzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23354"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01554-2017"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-11-1281"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.222"},{"issue":"4","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/oxfordjournals.jhered.a109937","article-title":"Inheritance of Brachydactyly Type D","volume":"75","author":"Gray E.","year":"1984","journal-title":"Journal of Heredity"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2011.12.013"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/374721"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0607-5"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201708"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2133476100"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2023.116860"},{"issue":"12","key":"e_1_2_12_13_1","first-page":"1073","article-title":"Brachydactyly and the Molecular Mechanisms of Digit Formation","volume":"41","author":"Lyu Z. 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