50P Monoallelic DAG1 truncating variants in patients with hyperCKemia

Dystroglycan is an essential component of the dystrophin-glycoprotein complex that links the actin-associated cytoskeleton to the extracellular matrix (ECM). Dystroglycan, encoded by the DAG1 gene, is proteolytically cleaved into α-Dystroglycan, a highly glycosylated protein that binds to ECM ligands, and β-Dystroglycan, a transmembrane protein non-covalently linked to α-Dystroglycan. Biallelic variants in DAG1 cause primary dystroglycanopathies with a wide phenotypic variability. Through exome sequencing we identified heterozygous truncating DAG1 variants in 18 individuals from 10 unrelated families. Five variants were stop gains and five were frameshift; with the majority localized in α-Dystroglycan (90%). Segregation analysis was available for seven families, with one variant being de novo, three dominantly inherited and three inherited from an asymptomatic parent. WGS performed in six patients excluded the presence of additional deep intronic DAG1 variants. The most common clinical features were the presence of high CK levels (18/18), myalgia (9/18) and muscle hypertrophy (3/18). Mild levels of learning or social difficulties were also observed in some patients (4/18). Histological analysis was performed in eight patients and showed the presence of mild dystrophic or myopathic changes. Dystroglycan immunostaining, either β-Dystroglycan or α-Dystroglycan, was reduced in four out of five patients. RNAseq data from muscle biopsies from two unrelated patients showed the expression of both wild-type and truncated alleles, indicating that nonsense-mediated decay is not triggered by these alleles. To date, few studies have reported the presence of heterozygous truncating DAG1 variants in asymptomatic or pauci-symptomatic individuals. Here, we describe 18 additional individuals with AD DAG1 hyperCKemia with mild muscular manifestations. Expression of both the truncated and wild-type alleles argues against haploinsufficiency as the underlying pathomechanisms in DAG1 -AD individuals.