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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Veröffentlicht in:Journal of human genetics 2024-08
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:1435-232X
1435-232X
DOI:10.1038/s10038-024-01284-z