Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

Abstract

Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype-phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient's phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype-phenotype correlations.

Keywords: RYR1-related myopathies; congenital myopathy; ryanodine receptor 1 (RYR1); splice variant; whole genome sequencing (WGS).

Figure 1

(A): The patient at the current age of 6 years, wheelchair-bound and with constant ventilation. (B): Pedigree of the patient (squares: male family members, circles: female members; crossed symbols: deceased family members; the affected individual is shown with a solid symbol and marked with an arrow).

Figure 2

(A–D). Histochemical staining of vastus lateralis muscle in the index patient performed 10 days after birth showed pathological alterations including enhanced presence of peri- and endomysial fat cells, vacuole alterations, fiber size variations, and few internal myonuclei in H&E and Trichrome (TC) staining. NADH and COX/SDH staining revealed enhanced central agglomeration of NADH and SDH in the muscle fibers. (E–H). Stainings of a normal control muscle biopsy performed 10 days after birth (scale bar 50 µm).

Figure 3

(A–D). Muscle biopsy of vastus lateralis muscle from patient 4 at the age of 9 years. Histochemical staining showed pathological alterations including presence of peri- and endomysial fat cells, fiber size variations with groups of atrophic fibers, internal myonuclei, and fiber splitting in H&E (A) and TC (B) staining. NADH (C) and COX/SDH (D) staining revealed enhanced central agglomeration of NADH and SDH in the muscle fibers building spoke-wheel–like structures (scalebar: 100 µm; control: Supplementary Figure S1). (E,F). MRI of the thigh and calves of patient 4 at the age of 9 years showing moderate, symmetric, reticular/streaky fat accumulation of lower limb muscles with involvement of quadriceps, biceps femoris, semitendinosus, semimembranosus, and soleus muscles and relative sparing of rectus femoris, gracilis, and tibialis posterior muscles. (G–J). Muscle biopsy of vastus lateralis muscle from patient 6 at the age of 1.5 years. Histochemical staining showed pathological alterations including presence of peri- and endomysial fat cells, fiber size variations, and fiber splitting in H&E (G) and TC (H) staining. Multiminicore-like alterations could be shown in NADH (I) and COX/SDH (J) staining (scalebar: 50 µm; control: Supplementary Figure S1). (K,L). MRI of the thigh and calves of patient 6 at the age of 13 years showing progressive, symmetric fat accumulation and atrophy of lower limb muscles with involvement of quadriceps, biceps femoris, semitendinosus, semimembranosus, and soleus muscles and relative sparing of adductor magnus, rectus femoris, gracilis, and tibialis posterior muscles.