{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:13:03Z","timestamp":1788322383334,"version":"build-2803163510"},"reference-count":14,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD118715"],"award-info":[{"award-number":["R01HD118715"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R21HD117520"],"award-info":[{"award-number":["R21HD117520"]}],"id":[{"id":"10.13039\/100009633","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"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Germline gain\u2010of\u2010function (GOF) variants in\n                    <jats:italic>ABL1<\/jats:italic>\n                    cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss\u2010of\u2010function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of\n                    <jats:italic>ABL1<\/jats:italic>\n                    \u2010related disorders. We report three individuals with\n                    <jats:italic>ABL1<\/jats:italic>\n                    variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a\n                    <jats:italic>de novo<\/jats:italic>\n                    likely pathogenic\n                    <jats:italic>ABL1<\/jats:italic>\n                    variant, NM_007313.2:c.354G&gt;T p.(Trp118Cys). We also provide updated clinical follow\u2010up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1\u2010related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with\n                    <jats:italic>ABL1<\/jats:italic>\n                    haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70293","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:16:16Z","timestamp":1788318976000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Functional Characterization of Gain\u2010of\u2010Function\n                    <scp>ABL1<\/scp>\n                    Variants Expands the Phenotypic Spectrum of\n                    <scp>CHDSKM<\/scp>"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-6200","authenticated-orcid":false,"given":"Yuri A.","family":"Zarate","sequence":"first","affiliation":[{"name":"Division of Genetics and Metabolism University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungjae","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Saldana Guzman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Paige","family":"Matheny","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Belgarde","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4734-3396","authenticated-orcid":false,"given":"Jenny P.","family":"Garzon","sequence":"additional","affiliation":[{"name":"Edwards Family Division of Genetics and Rare Diseases, Department of Pediatrics Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3348-3531","authenticated-orcid":false,"given":"Carlos E.","family":"Prada","sequence":"additional","affiliation":[{"name":"Edwards Family Division of Genetics and Rare Diseases, Department of Pediatrics Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoey","family":"Trueblood","sequence":"additional","affiliation":[{"name":"Southern California Permanente Medical Group  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moin U.","family":"Vera","sequence":"additional","affiliation":[{"name":"Southern California Permanente Medical Group  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2182-6843","authenticated-orcid":false,"given":"Konstantin V.","family":"Korotkov","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8743-026X","authenticated-orcid":false,"given":"Emilia","family":"Galperin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"6","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00439-024-02677-y","article-title":"Human ABL1 Deficiency Syndrome (HADS) is a Recognizable Syndrome Distinct From ABL1\u2010Related Congenital Heart Defects and Skeletal Malformations Syndrome","volume":"143","author":"AlAbdi L.","year":"2024","journal-title":"Human Genetics"},{"key":"e_1_2_10_3_1","first-page":"117954682514069","article-title":"Congenital Heart Defects and Skeletal Malformations Syndrome (CHDSKM) Associated With the ABL1 Gene in a Peruvian Patient: Case Report","volume":"19","author":"Arauco\u2010L\u00e1zaro D.","year":"2025","journal-title":"Clinical Medicine Insights: Cardiology"},{"issue":"4","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/s41431-020-00766-w","article-title":"Pathogenic Variants Causing ABL1 Malformation Syndrome Cluster in a Myristoyl\u2010Binding Pocket and Increase Tyrosine Kinase Activity","volume":"29","author":"Blakes A. J. M.","year":"2021","journal-title":"European Journal of Human Genetics"},{"issue":"10","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"e14782","DOI":"10.1097\/MD.0000000000014782","article-title":"Expanding the Clinical and Mutational Spectrum of Germline ABL1 Mutations\u2010Associated Syndrome: A Case Report","volume":"98","author":"Bravo\u2010Gil N.","year":"2019","journal-title":"Medicine (Baltimore)"},{"issue":"10","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1002\/humu.24075","article-title":"The Expanding Clinical Phenotype of Germline ABL1\u2010Associated Congenital Heart Defects and Skeletal Malformations Syndrome","volume":"41","author":"Chen C. A.","year":"2020","journal-title":"Human Mutation"},{"issue":"6","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"e63996","DOI":"10.1002\/ajmg.a.63996","article-title":"A Novel Missense Mutation of the ABL1 Gene in a Child With Congenital Heart Defects and Skeletal Malformations Syndrome","volume":"197","author":"Chen T. Y.","year":"2025","journal-title":"American Journal of Medical Genetics \u2010 Seminars in Medical Genetics, Part A"},{"issue":"10","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"e63718","DOI":"10.1002\/ajmg.a.63718","article-title":"Dandy\u2010Walker Malformation in an Individual With ABL1 Variant","volume":"194","author":"Garzon J. P.","year":"2024","journal-title":"American Journal of Medical Genetics \u2010 Seminars in Medical Genetics, Part A"},{"issue":"7","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1002\/ajmg.a.62194","article-title":"Further Delineation of Van den Ende\u2010Gupta Syndrome: Genetic Heterogeneity and Overlap With Congenital Heart Defects and Skeletal Malformations Syndrome","volume":"185","author":"Hildebrandt C. C.","year":"2021","journal-title":"American Journal of Medical Genetics \u2010 Seminars in Medical Genetics, Part A"},{"issue":"34","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"e2304611120","DOI":"10.1073\/pnas.2304611120","article-title":"A Biophysical Framework for Double\u2010Drugging Kinases","volume":"120","author":"Kim C.","year":"2023","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"1630894","DOI":"10.3389\/fcell.2025.1630894","article-title":"Haploinsufficiency of ABL1 Is Associated With Dominant Isolated Omphalocele","volume":"13","author":"Kolvenbach C. M.","year":"2025","journal-title":"Frontiers in Cell and Developmental Biology"},{"issue":"7","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"e20451","DOI":"10.1371\/journal.pone.0020451","article-title":"Predicting the Tolerated Sequences for Proteins and Protein Interfaces Using RosettaBackrub Flexible Backbone Design","volume":"6","author":"Smith C. A.","year":"2011","journal-title":"PLoS One"},{"issue":"6","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/ajmg.a.63189","article-title":"ABL1\u2010Related Congenital Heart Defects and Skeletal Malformations Syndrome in a Patient From Sub\u2010Saharan Africa: A Case Report Highlighting Novel Cardiac Features","volume":"191","author":"Spencer C.","year":"2023","journal-title":"American Journal of Medical Genetics. Part A"},{"issue":"4","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/ng.3815","article-title":"Germline Mutations in ABL1 Cause an Autosomal Dominant Syndrome Characterized by Congenital Heart Defects and Skeletal Malformations","volume":"49","author":"Wang X.","year":"2017","journal-title":"Nature Genetics"},{"issue":"1","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"W420","DOI":"10.1093\/nar\/gkac373","article-title":"IBS 2.0: An Upgraded Illustrator for the Visualization of Biological Sequences","volume":"50","author":"Xie Y.","year":"2022","journal-title":"Nucleic Acids Research"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70293","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70293","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:16:20Z","timestamp":1788318980000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":14,"alternative-id":["10.1002\/ajmg.a.70293"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70293","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-07-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ajmg.a.70293"}}