CACNA1S – Congenital Myopathy

CACNA1S (calcium channel voltage-dependent L-type alpha-1S subunit) encodes the Cav1.1 pore-forming subunit essential for excitation–contraction coupling in skeletal muscle (HGNC:1397). Congenital myopathies are a clinically and genetically heterogeneous group characterized by early onset hypotonia, muscle weakness, and structural muscle abnormalities (MONDO:0019952).

Several case reports have linked heterozygous CACNA1S variants to dominant congenital myopathy. A 58-year-old male developed late-onset limb-girdle weakness with vacuolar myopathy on biopsy; sequencing revealed c.3716G>A (p.Arg1239His) in exon 30 (PMID:35509735).

An autosomal recessive presentation was reported prenatally: a fetus with arthrogryposis, pulmonary hypoplasia, growth retardation and progressive hydrops carried compound heterozygous CACNA1S variants on WES; this is the first prenatal AR congenital myopathy/FADS case (PMID:38111203).

In a neonatal respiratory distress cohort of ventilated newborns with hypotonia, targeted neuromuscular panel sequencing diagnosed one patient with a predicted loss-of-function CACNA1S variant c.5104C>T (p.Arg1702Ter) among 28 cases (PMID:33667896).

A broader NGS study in 156 families with varied myopathy phenotypes identified a CACNA1S variant in one patient presenting with a milder or atypical congenital myopathy, underscoring inter-individual variability (PMID:34440373).

Taken together, four unrelated probands harboring heterozygous or biallelic CACNA1S variants support a limited but emerging association with congenital myopathy. Functional assays specific to congenital myopathy are lacking, and variant segregation is unreported. Further studies are needed to clarify pathogenic mechanisms and inform genetic counseling. Key take-home: CACNA1S variants should be considered in congenital myopathy gene panels, particularly for vacuolar and neonatal presentations.

References

• Cureus • 2022 • Short-Communication: Variable Expression of Clinical Symptoms and an Unexpected Finding of Vacuolar Myopathy Related to a Pathogenic Variant in the CACNA1S Gene in a Previous Case Report. PMID:35509735
• Prenatal diagnosis • 2023 • Biallellic variants in CACNA1S cause fetal akinesia sequence, progressive hydrops and stillbirth. PMID:38111203
• European journal of paediatric neurology • 2021 • Evaluating next-generation sequencing in neuromuscular diseases with neonatal respiratory distress. PMID:33667896
• Genes • 2021 • An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. PMID:34440373

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