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CACNA1S encodes the α1‐subunit of the dihydropyridine receptor and has been recently associated with Dihydropyridine receptor congenital myopathy (congenital myopathy 18; MONDO:0859514). In a consanguineous Turkish family, three siblings presented neonatal hypotonia, fixed flexion contractures, ophthalmoplegia and respiratory insufficiency. Whole‐exome sequencing identified a novel homozygous missense variant c.2366G>A (p.Arg789His) segregating with disease under an autosomal recessive model (PMID:31227654).
No functional assays have yet evaluated the p.Arg789His variant in skeletal muscle, and the pathogenic mechanism remains uncharacterized. Additional unrelated cases, extended segregation analyses, and in vitro or in vivo functional models will be critical to confirm causality. Key Take-home: Identification of CACNA1S c.2366G>A (p.Arg789His) expands its phenotypic spectrum to congenital myopathy and supports inclusion of CACNA1S in diagnostic panels for early‐onset neuromuscular disorders.
Gene–Disease AssociationLimitedSingle consanguineous family with three affected siblings and segregation of homozygous variant ([PMID:31227654]) Genetic EvidenceLimitedThree probands in one family with homozygous c.2366G>A (p.Arg789His) variant under autosomal recessive model Functional EvidenceNo evidenceNo functional studies reported for p.Arg789His variant in congenital myopathy context |