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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Bibliographic Details
Published in:Journal of human genetics 2025, Vol.70 (1), p.3-8
Main Authors: 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.
Format: Article
Language:English
Subjects:
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692/699/2732
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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
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Summary: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:1434-5161
1435-232X
1435-232X
DOI:10.1038/s10038-024-01284-z