A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps

Abstract

Background and purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant.

Methods: Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives.

Results: Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non-specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype.

Conclusion: Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.

Keywords: RYR1‐related myopathies; exercise intolerance; hyperCKemia; myalgia.

FIGURE 1

Seventeen individuals with the RYR1 p.Leu2286Val sharing a common haplotype. (a) Pedigrees of the seven families with p.Leu2286Val RYR1 (NM_000540.3:c.6856C>G). Arrows indicate index cases in each family. In families 5, 6 and 7, an in trans RYR1 variant with the p.Leu2286Val was detected (c.3619G>A, p.Val1207Met in 5.III.1, c.6359T>C, p.Met2120Thr in 6.II.1 and c.917C>T, p.Ala306Val in 7.I.2). (b) The genotype of index cases and available relatives of six selected SNPs spanning 147.8 kb. p.Leu2286Val‐associated haplotype is highlighted in yellow.

FIGURE 2

MRI patterns in RYR1 p.Leu2286Val patients. (a) Latissimus dorsi was mildly affected in patients 2.II.1 and 4.I.1 (white arrow). Paravertebral muscles were also involved in patient 2.II.1 (asterisk). (b) Glutei minimum involvement (white arrow), as well as iliacus hypertrophy (asterisk), were present in patients 1.II.4, 3.II.1 and 4.I.1. (c) In the thighs, the posterior compartment was more affected than the anterior, especially sartorius, adductor magnus and biceps femoris. Thigh hypertrophy was present in 1.II.4, 3.II.1 and 2.II.1. (d) In the legs, medial gastrocnemius (white arrows) was affected in patients 1.II.4, 2.II.1 and 4.I.1; soleus in patient 2.II.1 (asterisk) and tibialis anterior in patient 4.I.1.

FIGURE 3

Histological studies from muscle biopsies of patients 1.II.4 and 3.II.1. (a) Muscle biopsy from patient 1.II.4 showed variable‐size fibres with central nuclei and ring fibres (hematoxylin and eosin not shown). (b) Muscle biopsy of patient 3.II.1 showed central nuclei in a few fibres.