Introduction: Pathogenic variation in RYR1 is the most common cause of congenital myopathy. Clinical heterogeneity was noted between patients with RYR1-related myopathies, both in dominant and recessive inheritance. While phenotype variance among family members with the same variation was not fully understood. Method: Clinical, muscle pathologic and gene test data were collected and analyzed. Results: 64 patients were identified with dominant RYR1 variations from 10 families, patients scattered in at least three generations in 8 families. In 5 large families, there was at least 5 members involved, with 25 patients in the largest family. The clinical spectrum was highly variable among family members. Hereditary anticipation appeared in 7 families, as probands had earlier onset and more severe manifestation than their parents, and the motor ability of child usually worse than that of their parents. Ten missense pathogenic variations were identified, two out of them in exons 95, one in exon 100, one in exon 101, and six in exon 102. All located in Pore forming and PVSD domains. Discussion: Intra-family clinical diversity of RYR1 were observed in large families, and hereditary anticipation phenomenon was noticed with unknown mechanism. Modifying gene may exist encoding a protein nearing Pore forming domain of RyR1.

Xingzhi Chang
China

Cuijie Wei

Jieyu Liu

Yanbin Fan

Hui Xiong