Edition of 03 June 2026

A new study published in European Journal of Human Genetics characterized homozygous loss-of-function N-terminal truncating variants in the CACNB1 gene, which encodes β1 subunit of the skeletal muscle dihydropyridine receptor, a voltage-gated Ca2+ channel with a major role in excitation-contraction coupling. The variants were found among 3 individuals from 2 unrelated consanguineous families, with shared features of early-onset muscle weakness and wasting, hypotonia, elevated creatine kinase, dolichocephaly, narrow/cleft palate, ptosis and low body weight. Various analyses suggested that protein-truncating variants in this gene lead to a novel cause of inherited muscular disease.

A new study published in The American Journal of Human Genetics characterized biallelic loss-of-function variants in JKAMP, which encodes an ER-resident transmembrane protein involved in ER-associated degradation (ERAD). The variants were found among 14 affected individuals from 10 unrelated families with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and distinctive craniofacial features (round face with full cheeks, synophrys, epicanthus, bulbous nasal tip, long and smooth philtrum, full lips/open mouth with everted lower lip, and widely spaced teeth). Additional features were ocular involvements (manifesting as refractive errors, strabismus, nystagmus, or complex malformations). Various analyses established the role of JKAMP in human neurodevelopment and that variants in this gene cause pathogenic mechanism linking ER protein quality control to brain-enriched orphan G protein-coupled receptor regulation and neurological disease.