Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants

Tomoya Kubota, Miho Nagata, Kazuko Takagi, Yasuki Ishihara, Kurumi Kojima, Yuka Uchikura, Reina Yamamoto, Ayumi Yonei, Erina Ozaki, Natsuki Kira, Satoe Takahashi, Kazuaki Homma, Yohei Miyashita, Minenori Eguchi-Ishimae, Norio Sakai, Yohihiro Asano*, Yasushi Sakata, Keiichi Ozono, Mariko Eguchi*, Masanori P. Takahashi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3-8
Number of pages6
JournalJournal of Human Genetics
Volume70
Issue number1
DOIs
StatePublished - Jan 2025

Funding

This work was supported by the Initiative on Rare and Undiagnosed Diseases (IRUD) from the Japan Agency for Medical Research and Development (AMED) under number JP21ek0109549, a Research Grant for Intractable Disease from the Ministry of Health, Labour and Welfare of Japan (JP21FC1006, JP23FC1014) to MPT, and NIH grant DC017482 to KH.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants'. Together they form a unique fingerprint.

Cite this