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 language | English (US) |
---|---|
Pages (from-to) | 3-8 |
Number of pages | 6 |
Journal | Journal of Human Genetics |
Volume | 70 |
Issue number | 1 |
DOIs | |
State | Published - 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)