{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T05:28:44Z","timestamp":1765085324551,"version":"3.46.0"},"reference-count":39,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271666"],"award-info":[{"award-number":["82271666"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangdong Provincial Medical Science Research Fund Project","award":["B2025588"],"award-info":[{"award-number":["B2025588"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance:\u00a0FLNC encodes filamin C, a muscle-scaffolding protein crucial for cardiac integrity. Pathogenic FLNC variants cause diverse cardiomyopathies (hypertrophic, dilated, restrictive, and arrhythmogenic) and myofibrillar myopathies, but their role in congenital cardiac malformations is unclear. Notably, FLNC has not been implicated in structural defects such as Tetralogy of Fallot (TOF) to date. Case Presentation: Two fetuses from the same family were prenatally diagnosed with TOF via ultrasound. The trio whole-exome sequencing of the second fetus and her parents identified a novel heterozygous truncating FLNC variant (NM_001458.5:c.1453C&gt;T, p.Q485*). Sanger sequencing confirmed the same variant in the earlier TOF fetus. The mother carried the variant but was asymptomatic. In vitro mutagenesis in rat cardiomyocytes showed that the mutant FLNC construct produced markedly reduced FLNC proteins compared to the wild type and did not form abnormal cytoplasmic aggregates. Conclusions: We report on a novel FLNC truncating variant associated with fetal TOF, extending the spectrum of FLNC-related cardiac anomalies. The variable outcomes among variant carriers\u2014from fetal TOF to adult cardiomyopathy or no clinical manifestations\u2014underscore the complex genotype\u2013phenotype correlations of filaminopathy. This case highlights the importance of comprehensive genetic evaluation in families with diverse cardiac phenotypes and suggests that additional genetic factors likely influence phenotypic expression.<\/jats:p>","DOI":"10.3390\/diagnostics15243097","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T13:17:07Z","timestamp":1764940627000},"page":"3097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a Novel FLNC Truncating Variant in Fetal Tetralogy of Fallot: A Case Report and Review of the Literature"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7410-5049","authenticated-orcid":false,"given":"Zhiqiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Fang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linan","family":"Xu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shujing","family":"He","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi","family":"Ren","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Jia","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9701-3865","authenticated-orcid":false,"given":"Xiaoyan","family":"Liang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"},{"name":"Guangdong Engineering Technology Research Center of Fertility Preservation, Guangzhou 510655, China"},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/mgg3.488","article-title":"Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy","volume":"6","author":"Cui","year":"2018","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1002\/humu.23559","article-title":"De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy","volume":"39","author":"Kiselev","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.hrthm.2021.09.029","article-title":"Filamin-C variant-associated cardiomyopathy: A pooled analysis of individual patient data to evaluate the clinical profile and risk of sudden cardiac death","volume":"19","author":"Celeghin","year":"2022","journal-title":"Heart Rhythm"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/humu.22942","article-title":"Mutations in FLNC are associated with familial restrictive cardiomyopathy","volume":"37","author":"Brodehl","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/cge.13594","article-title":"FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations","volume":"96","author":"Ader","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of disease phenotypes resulting from multilocus genomic variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.1038\/s41467-019-12869-0","article-title":"Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders","volume":"10","author":"Oetjens","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1056\/NEJMoa1200395","article-title":"Phenotypic heterogeneity of genomic disorders and rare copy-number variants","volume":"367","author":"Girirajan","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jensen, M., and Girirajan, S. (2019). An interaction-based model for neuropsychiatric features of copy-number variants. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007879"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","unstructured":"Baban, A., Alesi, V., Magliozzi, M., Parlapiano, G., Genovese, S., Cicenia, M., Loddo, S., Lodato, V., Di Chiara, L., and Fattori, F. (2022). Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9100332"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.jacc.2016.09.927","article-title":"Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies","volume":"68","author":"Cuenca","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","first-page":"301","article-title":"ROD2 domain filamin C missense mutations exhibit a distinctive cardiac phenotype with restrictive\/hypertrophic cardiomyopathy and saw-tooth myocardium","volume":"76","author":"Carriel","year":"2023","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ytad572","DOI":"10.1093\/ehjcr\/ytad572","article-title":"A case series of patients with filamin-C truncating variants attending a specialized cardiac genetic clinic","volume":"7","author":"Hespe","year":"2023","journal-title":"Eur. Heart J. Case Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jensen, M., Smolen, C., Tyryshkina, A., Pizzo, L., Sun, J., Noss, S., Banerjee, D., Oetjens, M., Shimelis, H., and Taylor, C.M. (2025). Genetic modifiers and ascertainment drive variable expressivity of complex disorders. Cell.","DOI":"10.1016\/j.cell.2025.09.012"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e001584","DOI":"10.1161\/CIRCGENETICS.116.001584","article-title":"Screening of the filamin C gene in a large cohort of hypertrophic cardiomyopathy patients","volume":"10","author":"Lorca","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1161\/hc4601.098427","article-title":"NKX2. 5 mutations in patients with tetralogy of fallot","volume":"104","author":"Goldmuntz","year":"2001","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1002\/humu.22434","article-title":"GATA4 loss-of-function mutations underlie familial tetralogy of fallot","volume":"34","author":"Yang","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1172\/JCI8154","article-title":"Mutations in the cardiac transcription factor NKX2. 5 affect diverse cardiac developmental pathways","volume":"104","author":"Benson","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s11882-013-0384-6","article-title":"Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome","volume":"13","author":"Gao","year":"2013","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41390-023-02955-x","article-title":"Tetralogy of Fallot: Variants of MYH6 gene promoter and cellular functional analyses","volume":"96","author":"Zuo","year":"2024","journal-title":"Pediatr. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eadt0836","DOI":"10.1126\/sciadv.adt0836","article-title":"Loss-of-function variants in ciliary genes confer high risk for tetralogy of Fallot","volume":"11","author":"Zhou","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.jacc.2003.05.004","article-title":"NKX2.5 mutations in patients with congenital heart disease","volume":"42","author":"McElhinney","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/CIRCRESAHA.118.313250","article-title":"Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot","volume":"124","author":"Page","year":"2019","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.jacep.2017.12.003","article-title":"Filamin C truncation mutations are associated with arrhythmogenic dilated cardiomyopathy and changes in the cell\u2013cell adhesion structures","volume":"4","author":"Begay","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/humu.24004","article-title":"A mutation update for the FLNC gene in myopathies and cardiomyopathies","volume":"41","author":"Verdonschot","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.mayocp.2018.11.028","article-title":"A novel truncating variant in FLNC-encoded filamin C may serve as a proarrhythmic genetic substrate for arrhythmogenic bileaflet mitral valve prolapse syndrome","volume":"94","author":"Bains","year":"2019","journal-title":"Mayo Clin. Proc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jacbts.2016.05.004","article-title":"FLNC gene splice mutations cause dilated cardiomyopathy","volume":"1","author":"Begay","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1093\/hmg\/dds231","article-title":"Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy","volume":"21","author":"Ruparelia","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mao, Z., and Nakamura, F. (2020). Structure and function of filamin C in the muscle Z-disc. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082696"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1161\/CIRCULATIONAHA.119.044061","article-title":"Loss of filamin C is catastrophic for heart function","volume":"141","author":"Zhou","year":"2020","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wu, T., Xu, Y., Zhang, L., Liang, Z., Zhou, X., Evans, S.M., and Chen, J. (2023). Filamin C is essential for mammalian myocardial integrity. PLoS Genet., 19.","DOI":"10.1371\/journal.pgen.1010630"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1161\/CIRCRESAHA.123.322750","article-title":"Interaction of filamin C with actin is essential for cardiac development and function","volume":"133","author":"Zhou","year":"2023","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ydbio.2011.10.008","article-title":"Filamin C plays an essential role in the maintenance of the structural integrity of cardiac and skeletal muscles, revealed by the medaka mutant zacro","volume":"361","author":"Fujita","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1161\/01.RES.77.2.211","article-title":"Neural crest and cardiovascular patterning","volume":"77","author":"Kirby","year":"1995","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41569-018-0086-9","article-title":"The deployment of cell lineages that form the mammalian heart","volume":"15","author":"Meilhac","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5802\/crbiol.151","article-title":"On the involvement of the second heart field in congenital heart defects","volume":"347","author":"Guijarro","year":"2024","journal-title":"C. R. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/cvr\/cvae230","article-title":"Zebrafish arterial valve development occurs through direct differentiation of second heart field progenitors","volume":"121","author":"Derrick","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/cvr\/cvae249","article-title":"On the cusps of the second heart field: Insights from zebrafish into arterial valve origins and disease","volume":"121","author":"Kelly","year":"2025","journal-title":"Cardiovasc. Res."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/24\/3097\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T05:24:00Z","timestamp":1765085040000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/24\/3097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":39,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["diagnostics15243097"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15243097","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2025,12,5]]}}}