Sodium Channel Gene Variants in Fetuses with Abnormal Sonographic Findings: Expanding the Prenatal Phenotypic Spectrum of Sodium Channelopathies

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study,...

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Published in:	Genes Vol. 15; no. 1; p. 119
Main Authors:	Hadjipanteli, Andrea, Theodosiou, Athina, Papaevripidou, Ioannis, Evangelidou, Paola, Alexandrou, Angelos, Salameh, Nicole, Kallikas, Ioannis, Kakoullis, Kyriakos, Frakala, Sofia, Oxinou, Christina, Marnerides, Andreas, Kousoulidou, Ludmila, Anastasiadou, Violetta C, Sismani, Carolina
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-01-2024
Subjects:	Abnormalities, Multiple Amniotic fluid Channel gating Channelopathies Clubfoot Cohort analysis Cohort Studies DNA sequencing Epilepsy Female Fetus Fetus - diagnostic imaging Fetuses Genes Genetic disorders Genomes Genomics Genotype & phenotype Growth Growth rate Heterozygotes Humans Identification Lethality Medical prognosis Musculoskeletal system NAV1.4 Voltage-Gated Sodium Channel Nucleotide sequencing Phenotypes Pregnancy Pregnant women Sodium Sodium Channels Sodium channels (voltage-gated) Ultrasonic imaging Vitamins Cyprus severe fetal congenital myopathy 22B SCN4A SCN2A voltage-gated sodium channels whole-exome sequencing epileptic encephalopathy
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Summary:	Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study, we identified pathogenic variants in genes encoding the α subunit of VGSCs in the fetuses of two unrelated families with the use of trio-based whole exome sequencing, as part of a larger cohort study. Sanger sequencing was performed for variant confirmation as well as parental phasing. The fetus of the first family carried a known de novo heterozygous missense variant in the gene (NM_001040143.2:c.751G>A p.(Val251Ile)) and presented intrauterine growth retardation, hand clenching and ventriculomegaly. Neonatally, the proband also exhibited refractory epilepsy, spasms and MRI abnormalities. The fetus of the second family was a compound heterozygote for two parentally inherited novel missense variants in the gene (NM_000334.4:c.4340T>C, p.(Phe1447Ser), NM_000334.4:c.3798G>C, p.(Glu1266Asp)) and presented a severe prenatal phenotype including talipes, fetal hypokinesia, hypoplastic lungs, polyhydramnios, ear abnormalities and others. Both probands died soon after birth. In a subsequent pregnancy of the latter family, the fetus was also a compound heterozygote for the same parentally inherited variants. This pregnancy was terminated due to multiple ultrasound abnormalities similar to the first pregnancy. Our results suggest a potentially crucial role of the VGSC gene family in fetal development and early lethality.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4425 2073-4425
DOI:	10.3390/genes15010119