Loss-of-function variants in cause congenital myopathy with prominent facial and ocular involvement.

BACKGROUND

Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca homeostasis can contribute to disease pathology.

METHODS

We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples.

RESULTS

The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.DNA sequencing identified four unique homozygous loss-of-function variants in , encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs30, c.1738delC;p.Leu580Trpfs16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of in the F3 proband.

CONCLUSIONS

Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of results in a congenital myopathy with prominent facial, bulbar and ocular involvement.