P.443 - Identification and characterisation of ATP2A1 variants through whole exome sequencing

SERCA1 is a sarcoplasmic reticulum calcium transport ATPase encoded by ATP2A1. This enzyme facilitates muscle relaxation by catalysing calcium uptake from the cytosol to the sarcoplasmic reticulum lumen. Damaging recessive ATP2A1 mutations can decrease the efficiency with which the SERCA1 pump sequesters cytosolic calcium after muscle contraction. The resulting rare disorder, described in 1969 as Brody myopathy, is characterised by muscle cramping and an exercise-induced delay in muscle relaxation. We describe here the expansion of the genotype-phenotype correlation of Brody myopathy in two individuals with suspected pathogenic ATP2A1 variants. Whole exome sequencing (WES) was performed for 1 000 patients with undiagnosed limb-girdle muscle disease using Illumina exome capture; ATP2A1 was specifically examined for potentially pathogenic variants. Despite identifying 33 different ATP2A1 variants in 63 unrelated individuals, there were no homozygous variants and only two patients that harboured compound heterozygous changes. The patients were unrelated and both from the Basque Country in Spain. Patient 1 complained of exercise intolerance since childhood, with the development of myalgia, eyelid myokymia and mild lower limb proximal weakness. At 34 years old, patient 2 had a clinical onset of a metabolic myopathy with cramps and myalgia exacerbated after exercise. Both patients harboured novel or rare compound heterozygous ATP2A1 variants that could account for the disease: p.Glu121GlyfsTer3 and p.Arg822ProfsTer39 in patient 1, and p.Arg143Gln and p.Glu439AspfsTer80 in patient 2. The four mutations we report here are, to the best of our knowledge, completely novel in their association to Brody myopathy. The disease is an extremely rare, heterogeneous and debilitating disorder and our data have critically enhanced the emerging understanding of the genetic basis and the associated phenotype.