{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T11:07:09Z","timestamp":1789816029141,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2019 Telethon Grant (Cyprus)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study, we identified pathogenic variants in genes encoding the \u03b1 subunit of VGSCs in the fetuses of two unrelated families with the use of trio-based whole exome sequencing, as part of a larger cohort study. Sanger sequencing was performed for variant confirmation as well as parental phasing. The fetus of the first family carried a known de novo heterozygous missense variant in the SCN2A gene (NM_001040143.2:c.751G&gt;A p.(Val251Ile)) and presented intrauterine growth retardation, hand clenching and ventriculomegaly. Neonatally, the proband also exhibited refractory epilepsy, spasms and MRI abnormalities. The fetus of the second family was a compound heterozygote for two parentally inherited novel missense variants in the SCN4A gene (NM_000334.4:c.4340T&gt;C, p.(Phe1447Ser), NM_000334.4:c.3798G&gt;C, p.(Glu1266Asp)) and presented a severe prenatal phenotype including talipes, fetal hypokinesia, hypoplastic lungs, polyhydramnios, ear abnormalities and others. Both probands died soon after birth. In a subsequent pregnancy of the latter family, the fetus was also a compound heterozygote for the same parentally inherited variants. This pregnancy was terminated due to multiple ultrasound abnormalities similar to the first pregnancy. Our results suggest a potentially crucial role of the VGSC gene family in fetal development and early lethality.<\/jats:p>","DOI":"10.3390\/genes15010119","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T11:28:46Z","timestamp":1705577326000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sodium Channel Gene Variants in Fetuses with Abnormal Sonographic Findings: Expanding the Prenatal Phenotypic Spectrum of Sodium Channelopathies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4401-7513","authenticated-orcid":false,"given":"Andrea","family":"Hadjipanteli","sequence":"first","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4363-8162","authenticated-orcid":false,"given":"Athina","family":"Theodosiou","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Papaevripidou","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5565-0666","authenticated-orcid":false,"given":"Paola","family":"Evangelidou","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelos","family":"Alexandrou","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Salameh","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Kallikas","sequence":"additional","affiliation":[{"name":"AAK Ultrasound and Fetal Medicine Centre, 2025 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriakos","family":"Kakoullis","sequence":"additional","affiliation":[{"name":"Apollonion Private Hospital, 2054 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Frakala","sequence":"additional","affiliation":[{"name":"Ledra Clinic, 1060 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Oxinou","sequence":"additional","affiliation":[{"name":"Christina Oxinou Histopathology\/Cytology Laboratory, 1065 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Marnerides","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St Thomas\u2019 NHS Foundation Trust, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-262X","authenticated-orcid":false,"given":"Ludmila","family":"Kousoulidou","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violetta C.","family":"Anastasiadou","sequence":"additional","affiliation":[{"name":"Archbishop Makarios III Hospital, 2012 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9296-8347","authenticated-orcid":false,"given":"Carolina","family":"Sismani","sequence":"additional","affiliation":[{"name":"The Cyprus Institute of Neurology and Genetics, Cytogenetics and Genomics, 2371 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1212\/WNL.0b013e3181b9cebc","article-title":"De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies","volume":"73","author":"Ogiwara","year":"2009","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41583-020-00418-4","article-title":"Sodium channelopathies in neurodevelopmental disorders","volume":"22","author":"Meisler","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1684\/epd.2014.0641","article-title":"Confirming an expanded spectrum of SCN2A mutations: A case series","volume":"16","author":"Matalon","year":"2014","journal-title":"Epileptic Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e001817","DOI":"10.1161\/CIRCGEN.117.001817","article-title":"Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths","volume":"11","author":"Munroe","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7377","DOI":"10.1073\/pnas.1230273100","article-title":"Myasthenic syndrome caused by mutation of the SCN4A sodium channel","volume":"100","author":"Tsujino","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/1471-0528.16533","article-title":"The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies","volume":"128","author":"Kilby","year":"2021","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ogc.2017.10.003","article-title":"Whole Exome Sequencing: Applications in Prenatal Genetics","volume":"15","author":"Jelin","year":"2018","journal-title":"Obstet. Gynecol. Clin. N. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13073-022-01130-x","article-title":"Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: Clinical experience and lessons learned from a cohort of 1618 fetuses","volume":"14","author":"Fu","year":"2022","journal-title":"Genome Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103644","DOI":"10.1016\/j.ejmg.2019.04.001","article-title":"Next generation sequencing in recurrent pregnancy loss-approaches and outcomes","volume":"63","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Janicki, E., De Rademaeker, M., Meunier, C., Boeckx, N., Blaumeiser, B., and Janssens, K. (2023). Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges. Diagnostics, 13.","DOI":"10.3390\/diagnostics13050860"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/uog.24842","article-title":"Evolving fetal phenotypes and clinical impact of progressive prenatal exome sequencing pathways: Cohort study","volume":"59","author":"Mone","year":"2022","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_12","first-page":"GC01","article-title":"Cytogenetic analysis for suspected chromosomal abnormalities; A five years experience","volume":"10","author":"Polipalli","year":"2016","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e154942","DOI":"10.1172\/JCI154942","article-title":"Lessons learned: Next-generation sequencing applied to undiagnosed genetic diseases","volume":"132","author":"Schuler","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/ajmg.c.31989","article-title":"Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology","volume":"190","author":"Dhombres","year":"2022","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1136\/archdischild-2013-304340","article-title":"What is next generation sequencing?","volume":"98","author":"Behjati","year":"2013","journal-title":"Arch. Dis. Child. Educ. Pract. Ed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13073-018-0582-x","article-title":"Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder","volume":"10","author":"Normand","year":"2018","journal-title":"Genome Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41436-019-0731-7","article-title":"The use of fetal exome sequencing in prenatal diagnosis: A points to consider document of the American College of Medical Genetics and Genomics (ACMG)","volume":"22","author":"Monaghan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/pd.6115","article-title":"Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis","volume":"42","author":"Mellis","year":"2022","journal-title":"Prenat. Diagn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D1207","DOI":"10.1093\/nar\/gkaa1043","article-title":"The human phenotype ontology in 2021","volume":"49","author":"Gargano","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_21","unstructured":"Ellard, S., Baple, E.L., Callaway, A., Berry, I., Forrester, N., Turnbull, C., Owens, M., Eccles, D.M., Abbs, S., and Scott, R. (2023, December 20). ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020. Available online: https:\/\/www.acgs.uk.com\/media\/12443\/uk-practice-guidelines-for-variant-classification-v1-2023.pdf."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","article-title":"OMIM.org: Leveraging knowledge across phenotype-gene relationships","volume":"47","author":"Amberger","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The Human Genome Browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gonzalez-Quereda, L., Rodriguez, M.J., Diaz-Manera, J., Alonso-Perez, J., Gallardo, E., Nascimento, A., Ortez, C., Natera-De Benito, D., Olive, M., and Gonzalez-Mera, L. (2020). Targeted next-generation sequencing in a large cohort of genetically undiagnosed patients with neuromuscular disorders in Spain. Genes, 11.","DOI":"10.3390\/genes11050539"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1093\/brain\/awv352","article-title":"Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or \u201cclassical\u201d congenital myopathy","volume":"139","author":"Zaharieva","year":"2016","journal-title":"Brain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"809951","DOI":"10.3389\/fnmol.2022.809951","article-title":"SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis","volume":"15","author":"Zeng","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e152079","DOI":"10.1172\/JCI152079","article-title":"Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model","volume":"131","author":"Li","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10100","DOI":"10.1523\/JNEUROSCI.2476-06.2006","article-title":"Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures","volume":"26","author":"Scalmani","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1093\/brain\/awx054","article-title":"Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders","volume":"140","author":"Wolff","year":"2017","journal-title":"Brain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1111\/epi.12241","article-title":"An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current","volume":"54","author":"Lauxmann","year":"2013","journal-title":"Epilepsia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1212\/WNL.0b013e3181f8812e","article-title":"SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain","volume":"75","author":"Liao","year":"2010","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13229-020-00330-9","article-title":"SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: A role for pluripotent stem cells?","volume":"11","author":"Kruth","year":"2020","journal-title":"Mol. Autism"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1212\/WNL.0000000000001926","article-title":"SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures","volume":"85","author":"Howell","year":"2015","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.pediatrneurol.2013.07.004","article-title":"Novel de novo SCN2A mutation in a child with migrating focal seizures of infancy","volume":"49","author":"Dhamija","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ejpn.2017.01.014","article-title":"Unusual association of SCN2A epileptic encephalopathy with severe cortical dysplasia detected by prenatal MRI","volume":"21","author":"Bernardo","year":"2017","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.ejmg.2022.104639","article-title":"SCN2A and arrhythmia: A potential correlation? A case report and literature review","volume":"65","author":"Tzialla","year":"2022","journal-title":"Eur. J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/164_2017_52","article-title":"Sodium channelopathies of skeletal muscle","volume":"Volume 246","author":"Cannon","year":"2018","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e1405","DOI":"10.1212\/WNL.0000000000007185","article-title":"Myasthenic congenital myopathy from recessive mutations at a single residue in NaV1.4","volume":"92","author":"Elia","year":"2019","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Flood, E., Boiteux, C., and Allen, T.W. (2018). Selective ion permeation involves complexation with carboxylates and lysine in a model human sodium channel. PLoS Comput. Biol., 14.","DOI":"10.1371\/journal.pcbi.1006398"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:54Z","timestamp":1760104194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["genes15010119"],"URL":"https:\/\/doi.org\/10.3390\/genes15010119","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]}}}