{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:01:22Z","timestamp":1790870482504,"version":"4.1.0"},"reference-count":14,"publisher":"Ordem dos Medicos","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Acta Med Port"],"abstract":"<jats:p>To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C&gt;T p.Ala360Val, likely pathogenic, and c.1258G&gt;A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.<\/jats:p>","DOI":"10.20344\/amp.23831","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T13:36:49Z","timestamp":1779111409000},"page":"644-648","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype"],"prefix":"10.20344","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-5481","authenticated-orcid":false,"given":"Joana","family":"Capela","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0776-8819","authenticated-orcid":false,"given":"Mariana","family":"Reis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9128-3469","authenticated-orcid":false,"given":"In\u00eas","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-0914","authenticated-orcid":false,"given":"Marta","family":"Novo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ramalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9197-7586","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Lipari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-2524","authenticated-orcid":false,"given":"M\u00e1rcia","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"8464","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"12855","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.660076"},{"key":"12856","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0689-3"},{"key":"12857","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2018_89"},{"key":"12858","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-019-01834-5"},{"key":"12859","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07067-3"},{"key":"12860","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22590"},{"key":"12861","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.7184"},{"key":"12862","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23398"},{"key":"12863","doi-asserted-by":"publisher","DOI":"10.1080\/03009734.2019.1670297"},{"key":"12864","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951124025095"},{"key":"12865","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-019-0798-7"},{"key":"12866","unstructured":"Ferreira SL, Ferreira ST, Silva PG, Estrada J, Virella D, Casimiro A, et al. A case report of vars2-related encephalocardiomyopathy: expanding the phenotype. 2023. [cited 2025 Aug 21]. Available from: https:\/\/anuariohde.com\/index.php\/component\/k2\/item\/3090-a-case-report-of-vars2-related-encephalocardiomyopathy-expanding-the-phenotype."},{"key":"12867","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.70053"},{"key":"12868","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-017-0124-4"}],"container-title":["Acta M\u00e9dica Portuguesa"],"original-title":[],"link":[{"URL":"https:\/\/www.actamedicaportuguesa.com\/revista\/index.php\/amp\/article\/download\/23831\/15958","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.actamedicaportuguesa.com\/revista\/index.php\/amp\/article\/download\/23831\/15959","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:41:01Z","timestamp":1790869261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.actamedicaportuguesa.com\/revista\/index.php\/amp\/article\/view\/23831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":14,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.20344\/amp.23831","relation":{},"ISSN":["1646-0758","0870-399X"],"issn-type":[{"value":"1646-0758","type":"electronic"},{"value":"0870-399X","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5,18]]}}}