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Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants
Hydrops fetalis, characterized by abnormal fluid accumulation in fetuses, presents a significant risk of stillbirth and neonatal mortality. Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study f...
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| Published in: | Journal of human genetics 2025, Vol.70 (1), p.3-8 |
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| creator | Kubota, Tomoya Nagata, Miho Takagi, Kazuko Ishihara, Yasuki Kojima, Kurumi Uchikura, Yuka Yamamoto, Reina Yonei, Ayumi Ozaki, Erina Kira, Natsuki Takahashi, Satoe Homma, Kazuaki Miyashita, Yohei Eguchi-Ishimae, Minenori Sakai, Norio Asano, Yohihiro Sakata, Yasushi Ozono, Keiichi Eguchi, Mariko Takahashi, Masanori P. |
| description | Hydrops fetalis, characterized by abnormal fluid accumulation in fetuses, presents a significant risk of stillbirth and neonatal mortality. Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study focused on a family with three consecutive stillbirths, each with pronounced hydrops fetalis. Using whole-exome sequencing (WES), we identified compound heterozygous variants of the
SCN4A
gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of
SCN4A
variants in NIHF and underscore the significance of functional studies in elucidating genotype-phenotype correlations. Furthermore, our study emphasizes the diagnostic value of WES in cases of NIHF in where standard genetic testing fails to identify causative variants. |
| doi_str_mv | 10.1038/s10038-024-01284-z |
| format | article |
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SCN4A
gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of
SCN4A
variants in NIHF and underscore the significance of functional studies in elucidating genotype-phenotype correlations. Furthermore, our study emphasizes the diagnostic value of WES in cases of NIHF in where standard genetic testing fails to identify causative variants.</description><identifier>ISSN: 1434-5161</identifier><identifier>ISSN: 1435-232X</identifier><identifier>EISSN: 1435-232X</identifier><identifier>DOI: 10.1038/s10038-024-01284-z</identifier><identifier>PMID: 39164360</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>45 ; 45/23 ; 692/699/2732 ; 692/699/375/374 ; 9/74 ; Biomedical and Life Sciences ; Biomedicine ; Channel gating ; Channel opening ; Fetuses ; Gene Expression ; Gene Function ; Gene Therapy ; Genetic factors ; Genotypes ; Human Genetics ; Hydrops ; Hydrops fetalis ; Molecular Medicine ; Neonates ; Pathogenicity ; Phenotypes ; Skeletal muscle ; Sodium channels ; Sodium channels (voltage-gated) ; Whole genome sequencing</subject><ispartof>Journal of human genetics, 2025, Vol.70 (1), p.3-8</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>Copyright Nature Publishing Group Jan 2025</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c400t-d8ca6af4d254b9978d88abc4f40217a353b11862d4711c291d50e916e8b596043</cites><orcidid>0000-0002-5513-5012 ; 0000-0002-4440-2277 ; 0000-0001-8727-1732 ; 0000-0002-6517-8825</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39164360$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kubota, Tomoya</creatorcontrib><creatorcontrib>Nagata, Miho</creatorcontrib><creatorcontrib>Takagi, Kazuko</creatorcontrib><creatorcontrib>Ishihara, Yasuki</creatorcontrib><creatorcontrib>Kojima, Kurumi</creatorcontrib><creatorcontrib>Uchikura, Yuka</creatorcontrib><creatorcontrib>Yamamoto, Reina</creatorcontrib><creatorcontrib>Yonei, Ayumi</creatorcontrib><creatorcontrib>Ozaki, Erina</creatorcontrib><creatorcontrib>Kira, Natsuki</creatorcontrib><creatorcontrib>Takahashi, Satoe</creatorcontrib><creatorcontrib>Homma, Kazuaki</creatorcontrib><creatorcontrib>Miyashita, Yohei</creatorcontrib><creatorcontrib>Eguchi-Ishimae, Minenori</creatorcontrib><creatorcontrib>Sakai, Norio</creatorcontrib><creatorcontrib>Asano, Yohihiro</creatorcontrib><creatorcontrib>Sakata, Yasushi</creatorcontrib><creatorcontrib>Ozono, Keiichi</creatorcontrib><creatorcontrib>Eguchi, Mariko</creatorcontrib><creatorcontrib>Takahashi, Masanori P.</creatorcontrib><title>Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants</title><title>Journal of human genetics</title><addtitle>J Hum Genet</addtitle><addtitle>J Hum Genet</addtitle><description>Hydrops fetalis, characterized by abnormal fluid accumulation in fetuses, presents a significant risk of stillbirth and neonatal mortality. Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study focused on a family with three consecutive stillbirths, each with pronounced hydrops fetalis. Using whole-exome sequencing (WES), we identified compound heterozygous variants of the
SCN4A
gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of
SCN4A
variants in NIHF and underscore the significance of functional studies in elucidating genotype-phenotype correlations. Furthermore, our study emphasizes the diagnostic value of WES in cases of NIHF in where standard genetic testing fails to identify causative variants.</description><subject>45</subject><subject>45/23</subject><subject>692/699/2732</subject><subject>692/699/375/374</subject><subject>9/74</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Channel gating</subject><subject>Channel opening</subject><subject>Fetuses</subject><subject>Gene Expression</subject><subject>Gene Function</subject><subject>Gene Therapy</subject><subject>Genetic factors</subject><subject>Genotypes</subject><subject>Human Genetics</subject><subject>Hydrops</subject><subject>Hydrops fetalis</subject><subject>Molecular Medicine</subject><subject>Neonates</subject><subject>Pathogenicity</subject><subject>Phenotypes</subject><subject>Skeletal muscle</subject><subject>Sodium channels</subject><subject>Sodium channels (voltage-gated)</subject><subject>Whole genome sequencing</subject><issn>1434-5161</issn><issn>1435-232X</issn><issn>1435-232X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNp9kUtr3DAUhUVoyPsPdFEE3XTjqa4etrwqJTRJITSbBLIJQpbkGQePNJXsgZlfH82jSdNFV_fC_e6Rzj0IfQQyAcLk1wQkl4JQXhCgkhfrA3QCnImCMvr4YdvzQkAJx-g0pWeScVrRI3TMaig5K8kJerpZ2RgWCbdu0H2XsB0dHgLuQ0o4tLgdvRm64Df97JdewoRjM9Peux4vO41NmC_C6C2eucHFsF5Nw5jwUsdO-yGdo8NW98ld7OsZerj6cX95U9zeXf-8_H5bGE7IUFhpdKlbbqngTV1X0kqpG8NbTihUmgnWAMiSWl4BGFqDFcRlC042oi4JZ2fo2053MTZzZ43zQ9S9WsRuruNKBd2p9xPfzdQ0LBVARYhkZVb4sleI4ffo0qDmXTKu77V32ZFipBZQcSo26Od_0OcwRp_9KQb52pKKLUV3lIn5lNG1r78BojbxqV18KsentvGpdV769LeP15U_eWWA7YCUR37q4tvb_5F9AR9bpmk</recordid><startdate>2025</startdate><enddate>2025</enddate><creator>Kubota, Tomoya</creator><creator>Nagata, Miho</creator><creator>Takagi, Kazuko</creator><creator>Ishihara, Yasuki</creator><creator>Kojima, Kurumi</creator><creator>Uchikura, Yuka</creator><creator>Yamamoto, Reina</creator><creator>Yonei, Ayumi</creator><creator>Ozaki, Erina</creator><creator>Kira, Natsuki</creator><creator>Takahashi, Satoe</creator><creator>Homma, Kazuaki</creator><creator>Miyashita, Yohei</creator><creator>Eguchi-Ishimae, Minenori</creator><creator>Sakai, Norio</creator><creator>Asano, Yohihiro</creator><creator>Sakata, Yasushi</creator><creator>Ozono, Keiichi</creator><creator>Eguchi, Mariko</creator><creator>Takahashi, Masanori P.</creator><general>Springer Nature Singapore</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5513-5012</orcidid><orcidid>https://orcid.org/0000-0002-4440-2277</orcidid><orcidid>https://orcid.org/0000-0001-8727-1732</orcidid><orcidid>https://orcid.org/0000-0002-6517-8825</orcidid></search><sort><creationdate>2025</creationdate><title>Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants</title><author>Kubota, Tomoya ; 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Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study focused on a family with three consecutive stillbirths, each with pronounced hydrops fetalis. Using whole-exome sequencing (WES), we identified compound heterozygous variants of the
SCN4A
gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of
SCN4A
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| subjects | 45 45/23 692/699/2732 692/699/375/374 9/74 Biomedical and Life Sciences Biomedicine Channel gating Channel opening Fetuses Gene Expression Gene Function Gene Therapy Genetic factors Genotypes Human Genetics Hydrops Hydrops fetalis Molecular Medicine Neonates Pathogenicity Phenotypes Skeletal muscle Sodium channels Sodium channels (voltage-gated) Whole genome sequencing |
| title | Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants |
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