LIMB GIRDLE MUSCULAR DYSTROPHIES: P.156 Differences in demographic and phenotypic spectrum of genetically solved and unsolved cases in a large cohort of patients with limb girdle weakness

Abstract

Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic neuromuscular disorders. Whole exome sequencing (WES) in the MYO-SEQ project achieved a diagnostic yield of approximately 50%, leaving a considerable number of patients undiagnosed. We performed phenotypic and demographic studies in a cohort of 1891 patients with limb girdle weakness. WES was done at the Broad Institute of MIT and Harvard's Genomics Platform. Phenotypic data collection was performed using the PhenoTips online platform. Age structure showed a higher percentage of late onset muscle diseases in the unsolved cohort (36%) in comparison to the solved cohort (14%). On the other hand, early onset patients (including congenital, infantile and childhood onset), showed a lower percentage in the unsolved cohort (26%) in comparison to the solved cohort (32%). Normal creatine kinase (CK) levels were more prevalent in the unsolved cohort (20%) in comparison to the solved cohort (11%), whereas CK levels elevated more than 10x were more prevalent in the solved cohort (28%) than in the unsolved cohort (15%). In both cohorts, the heterozygous carrier frequency of known pathogenic variants in three recessive genes with high pathogenic allele frequency, CAPN3, ANO5 and GAA, was investigated. This was 3.5-4.5x higher in the unsolved than in the solved cases. The allele frequencies in the unsolved cohort were CAPN3 0.0106 (vs. 0.003 in solved), ANO5 0.0113 (vs. 0.003 in solved) and GAA 0.009 (vs. 0.002 in solved) (p<0.005). Higher pathogenic carrier frequency in the unsolved sub-cohort may indicate the presence of a second cryptic disease–causing variant, not detected by exome sequencing. Patients with late onset and normal CK levels are more common in the unsolved cohort. This may suggest that these are actually acquired diseases. Applying whole genome sequencing, RNA-Seq and immunoanalysis can help to diagnose the unsolved cohort.