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However, our current understanding of the genetic etiology for TOF is limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing (WES) and Sanger sequencing were applied to a family trio diagnosed with TOF by fetal prenatal ultrasound examination. A minigene assay was performed to confirm the splicing defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified compound heterozygous variants in the <jats:italic>cerebral cavernous malformation 2\u2010like<\/jats:italic> (<jats:italic>CCM2L<\/jats:italic>) gene, namely the paternally inherited nonsense variant NM_001365692.1:c.741G&gt;A p.(Trp247Ter) and the maternally inherited splice\u2010site variant NM_001365692.1:c.1263+2T&gt;A in a fetus with TOF featuring a ventricular septal defect associated with overriding aorta and pulmonary stenosis. Minigene assay showed that the c.1263+2T&gt;A variant led to skipping of <jats:italic>CCM2L<\/jats:italic> exon8 during RNA splicing, which is thought to result in frameshift and premature termination of translation. Both variants were absent from the public population databases (Genome Aggregation Database [gnomAD], 1000 Genomes [1000G], Clinvar) and classified as likely pathogenic according to the ACMG guidelines (PVS1\u2009+\u2009PM2 level evidence).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>To our knowledge, this is the first reported case of biallelic loss\u2010of\u2010function variants in human <jats:italic>CCM2L<\/jats:italic>. Our findings suggest a potential association of human <jats:italic>CCM2L<\/jats:italic> with TOF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70117","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T12:13:39Z","timestamp":1750076019000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Compound Heterozygous Loss\u2010of\u2010Function Variants in <scp><i>CCM2L<\/i><\/scp> in a Fetus With Tetralogy of Fallot"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6856-4281","authenticated-orcid":false,"given":"Dandan","family":"Ling","sequence":"first","affiliation":[{"name":"Clinical Research Center for Placental Medicine in Hunan Province  Changsha Hunan China"},{"name":"Department of Obstetrics Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-8277","authenticated-orcid":false,"given":"Wanqin","family":"Xie","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1455-0858","authenticated-orcid":false,"given":"Xiao","family":"Mao","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyu","family":"Liu","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yabing","family":"Tang","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Placental Medicine in Hunan Province  Changsha Hunan China"},{"name":"Department of Obstetrics Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanjuan","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Medical Record Management Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.1012665"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110571"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742\u20134658.2009.07536.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010024\u201001626\u20107"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1510495112"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjcpc.2023.12.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.304458"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg\u20102024\u2010110212"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742\u20104658.2009.07535.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.01.006"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2005.061143"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.124"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1104"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.06.004"}],"container-title":["Molecular Genetics &amp; 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