Novel truncating variant in DNA2-related congenital onset myopathy and ptosis suggests genotype-phenotype correlation.

DNA2 encodes a protein with nuclease, ATPase, and helicase domains, and serves to maintain mitochondrial DNA integrity. Mutations in DNA2 cause autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions. This disorder was first reported in four patients with heterozygous, missense mutations in DNA2. Clinical symptoms include limb-girdle and lower extremity weakness, myalgia, and ophthalmoplegia. All had a slowly progressive disease course and did not present for clinical evaluation until the fifth or sixth decade. We report a case of congenital-onset myopathy and ptosis in a child who was found to have a novel DNA2 variant resulting in a premature termination codon (p.Asn568Ilefs*4). Only one other case of a truncating mutation in DNA2 has been reported, and that patient also had early-onset, severe disease. We hypothesize that haploinsufficiency for the DNA2 protein due to truncating mutations results in mitochondrial genome instability and clinical symptoms of early-onset myopathy. Missense mutations that allow for residual protein function lead to a milder clinical phenotype.