Genotype-phenotype correlations in recessive RYR1-related myopathies

Table 3 An analysis of the position of all recessive non-hypomorphic RYR1 mutations vs severity & ophthalmoparesis

	Mutations associated with mild phenotypes/total cohort	Percentage of mutations with mild phenotypes (CI)	Mutations associated with ophthalmoplegia/	Percentage of mutations associated with ophthalmoplegia (CI)
	Mutations associated with mild phenotypes/total cohort	Percentage of mutations with mild phenotypes (CI)	Total mutations
Total cohort*	46/67	68.7	43/102	42.2
Domain
Combined MH/CCD hotspot domains	21/35	60 (44–74)	17/52	33 (21–46)
Hotspot domain 1	9/12	75 (46–92)	6/16	38 (18–61)
Hotspot domain 2	4/4	100 (54–100)	2/10	20 (5–52)
Hotspot domain 3	8/19	42 (23–64)	9/26	35 (19–54)
Interdomain interactions	1/1	100 (22–100)	1/1	100 (22–100)
Triadin	0/3	0 (0–53)	2/7	29 (8–65)
DHPR	9/10	90 (46–100)	5/20	25 (11–47)
S100A1	2/2	100 (22–100)	1/5	20 (2–64)
apoCaM	4/4	100 (37–100)	4/7	57 (25–84)
CaCaM	0/0	-	0/1	0 (0–78)
SPRY domains	3/5	60 (17–92)	7/11	64 (35–85)

Severity scores between 0 and 4 were classed as mild and scores between 5 and 8 were classed as severe (Additional file 3: Table S3). Two results in the analysis of disease severity vs mutation domain deviated significantly from expected ratios. Mutations in MH/CCD hotspot 3 and in the triadin binding domain (with sits within hotspot 3) were associated with a severe phenotype more often than expected by chance. There was no evidence that non-hypomorphic mutations in specific domains were associated with a greater or lower chance of ophthalmoparesis. * To reduced bias, each non-hypomorphic recessive RYR1 mutation was counted only once, even if several individuals have been reported with the mutation. For the analysis of phenotype severity, severity scores were averaged when severity data was available on several individuals with a mutation. For the analysis of ophthalmoparesis, mutations were classified as associated with ophthalmoplaresis if any patient with the mutation was reported to have ophthalmoparesis. CI = 95% Wilson confidence intervals. Bold font shows where results are significantly different from expected ratios.

ISSN: 1750-1172