Identification of a novel compound heterozygous mutation in RyR1 gene in
an Indian family affected with congenital myopathy
Abstract
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;
13423_13424del: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.