New Compound Heterozygous Splice Site Mutations of the Skeletal Muscle Ryanodine Receptor (RYR1) Gene Manifest Fetal Akinesia: A Linkage with Congenital Myopathies

Abstract

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been linked to malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. RYR1 is an intracellular calcium release channel and plays a crucial role in the sarcoplasmic reticulum and transverse tubule connection. Here, we report 2 fetuses from the same parents with compound heterozygous mutations in the RYR1 gene (c.10347+1G>A and c.10456-2Α>G) who presented with fetal akinesia and polyhydramnios at 27 and 19 weeks of gestation with intrauterine growth restriction in the third pregnancy. The prospective parents of the fetuses were heterozygous carriers for c.10456-2Α>G (mother) and c.10347+1G>A (father). Both mutations affect splice sites resulting in dysfunctional protein forms probably missing crucial domains of the C-terminus. Our findings reveal a new RYR1 splice site mutation (c.10456-2Α>G) that may be associated with the clinical features of myopathies, expanding the RYR1 spectrum related to these pathologies.

Keywords: Compound heterozygous mutations; Fetal akinesia; Myopathies; Next-generation sequencing; Skeletal muscle ryanodine receptor.

Fig. 1

Family tree of patients and carriers of mutations in the RYR1 gene. The father (I-1) is a heterozygous carrier for mutation c.10347+1G>A and the mother (I-2) is a heterozygous carrier for mutation c.10456-2Α>G in the RYR1 gene. II-1: asymptomatic male child. II-2: affected female neonate that died soon after birth and was found as compound heterozygous for both parental mutations in RYR1. II-3: affected fetus with a c.10347+1G>A and a c.10456-2A>G mutation in heterozygous state in the RYR1 gene. II-IV: asymptomatic female child, heterozygous carrier only for the father's mutation in RYR1 (c.10347+1G>A).

Fig. 2

IGV screenshot of II-3 for intronic mutations in RYR1 after NGS analysis. A Mutation c.10347+1G>A in RYR1 in heterozygous state (inherited from the father). B Mutation c.10456-2A>G in RYR1 in heterozygous state (inherited from the mother).

Fig. 3

Sanger sequencing data. A Mutation c.10347+1G>A in the RYR1 gene in heterozygous state (father). B Mutation c.10456-2A>G in the RYR1 gene in heterozygous state (mother).