Genetic Landscape and Diagnostic Outcomes of UK Patients With Congenital Myopathies and Muscular Dystrophies Over a 10-Year Period

Figures

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  Figure 1. Flowchart of Referral Outcomes in the 10-Year Period Percentages expressed refer to the total cohort of patients.

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  Figure 2. Yearly Diagnostic Outcomes and Yields

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  Figure 3. Genetically Diagnosed Patients Frequencies of genetically diagnosed CMYO or CMD due to variant/s in other genes: INPP5K (1.3%), PIEZO2 (1.1%), MSTO1 (0.9%), COL12A1 (0.7%), ECEL1 (0.7%), CACNA1s (0.6%), MYBPC (0.6%), TNNT1 (0.6%) CFL2 (0.4%), LMOD3 (0.4%), MEGF10 (0.4%), MYH8 (0.4%), and SCN4A (0.4%). Pathogenic variants in the following genes were also identified in 1 patient, each: BIN1, FXR1, HACD1, KHL41, STIM1, TNNT2, TNNT3, TRIP4, UNC45B, ZC4H2, CHKB, CIAO1, FHL1, FKBP14, GGPS1, MICU1, PLEC1, and TMEM. CMD = congenital muscular dystrophy; CMYO = congenital myopathy.

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  Figure 4. Details of the Composition of the CMYO and CMD Populations (A) Relative prevalence of CMYO: the “Other gene” category includes the following genes (with prevalence indicated in brackets)—PIEZO2 (1.7%), ECEL1 (1.2%), CACNA1s (0.9%), MYBPC (0.9%), TNNT1 (0.9%), CFL2 (0.6%), LMOD3 (0.6%), MEGF10 (0.6%), MYH8 (0.6%), and SCN4A (0.6%). Pathogenic variants in 11 additional genes were also identified in 1 patient, each: BIN1, FXR1, HACD1, KHL41, STIM1, TNNT2, TNNT3, TRIP4, UNC45B, ZC4H2, and COL25A1. (B) Relative prevalence of CMD: the “Other gene” category includes the following genes (with prevalence indicated in brackets)—INPP5K (3.4%), MSTO1 (2.4%), and COL12A1 (1.9%). Pathogenic variants in 8 additional genes were also identified in 1 patient, each: CHKB, CIAO1, FHL1, FKBP14, GGPS1, MICU1, PLEC1, and TMEM. The full list of genes included in COL6-RD and Alfa-DG groups and relative prevalence are detailed in the table on the right. CMD = congenital muscular dystrophy; CMYO= congenital myopathy.

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  Figure 5. Distribution of Heterozygous Pathogenic Variants in Recessive Genes The “Other gene” category includes 13 additional genes (COL6A3, EPG5, FKRP, GMPPB, KLHL40, LMOD3, MICU1, MYMK, MYO18B, PIEZO2, RYR1, SPEG, TRIP4), with 1 patient carrying a single variant in each of these genes.

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  Figure 6. Relative Frequencies of VUS The “Other gene” category includes the following genes (with prevalence indicated in brackets): POMT1 (0.8%), DNM2 (0.8%), MYBPC3 (0.8%), PLEC1 (0.8%), SCN4A (0.8%), MTM1 (0.7%), LMOD3 (0.7%), GMPPB (0.7%), MSTO1 (0.7%), STIM1 (0.7%), VPS33B (0.7%), KLHL40 (0.5%), BIN1 (0.5%), CCDC78 (0.5%), DNA2 (0.5%), ISPD (0.5%), ORAI1 (0.5%), TNNT1 (0.5%), and MYMK (0.3%). VUS in additional 21 genes (MYMK, DAG, FKBP14, FKRP, KHL41, MICU1, SRPK3, STAC3, TPM3, TRAPPC1, CFL2, FKTN, GOLGA2, GTDC, POMGnT1, POMGnT2, RYR3, TNNT3, TPM2, TRIP4, TRPV4, and ZC4H2) were found in <2 patients, each.