Identification of a novel compound heterozygous mutation in RyR1 gene in an Indian family affected with congenital myopathy

Within the ryanodine receptor family (RyR), three genes (RyR1, RyR2, and RyR3) are involved in Ca2+ homeostasis, storage, and regulation. Mutations in RyR1 causes a wide range of clinical phenotypes, including several congenital myopathies (CM), central core disease (CCD), and hyperthermia susceptibility. RyR1-related CCDs usually show clinical heterogeneity and an early onset of disease pathogenesis. Here, we present a family that includes unaffected parents and three siblings who have been affected with muscle problems since childhood. The clinical features include lower proximal muscle weakness, difficulties in standing up and climbing, skeletal malformations and hypotonia. Clinical examinations (e. g. , nerve conduction velocity, electromyography, and muscle magnetic resonance imaging) showed weak muscle intensity, activity, and muscle atrophy. Whole-exome sequencing was performed in two affected siblings along with unaffected mother in the family using Illumina NovaSeq2500. Bioinformatic analysis and filtering of multiple variants revealed a novel variant in RyR1. This compound heterozygous variant (c. A5096G: p. D1699G+c. C5097AA: pD1699E; 13423₁3424del: p. K4475Efs*106) has not been reported in public databases and in silico analysis predicted that the variant is damaging. Furthermore, this novel variant segregates within the family and in silico protein analysis showed putative changes in the protein activity between the wildtype versus mutant RyR1. The initial functional analysis showed changes in calcium channel activity, however, additional confirmational assays are required. Our study explains a genotype-phenotype correlation in the family. It expands the requisite prenatal diagnosis in the family and in the near future will provide a platform for therapeutics in RyR1-related diseases.