The Homozygous c.612C>G Mutation in C1QBP is Associated with Late-Onset Progressive External Ophthalmoplegia

Biallelic pathogenic variants in C1QBP are an infrequent, yet increasingly recognised, cause of progressive external ophthalmoplegia (PEO). Although most published cases include cardiomyopathy, isolated late‑onset PEO without cardiac disease remains exceptional. To characterise, for the first time, a Moldavian‑Ukrainian pedigree in which homozygous c.612C>G (p.Phe204Leu) in C1QBP causes autosomal‑recessive PEO in the absence of cardiomyopathy, thereby expanding the phenotypic spectrum of C1QBP‑related disease. We performed a comprehensive clinical evaluation, needle electromyography, and targeted next-generation sequencing with segregation analysis in seven relatives, complemented by short-tandem-repeat profiling to assess parental relatedness. Three siblings (15–28 y) were homozygous for c.612C>G; four relatives were heterozygous and asymptomatic. Affected individuals shared bilateral ptosis, variable limb-girdle weakness, and gastrointestinal dysmotility, but routine echocardiography and electrocardiography were normal. EMG showed chronic myopathic potentials with reduced duration/amplitude in distal lower‑limb muscles. In‑silico prediction, extremely low allele frequency (0.005%), and segregation fulfilled ACMG class 5 (pathogenic). Our report represents one of the few families with C1QBP‑related PEO without cardiomyopathy reported to date. These findings underline the importance of including C1QBP in diagnostic panels for apparently isolated PEO and illustrate the utility of family‑based genome analysis for precision counselling and management.