Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With...

Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies caused by impaired glycosylation of α-dystroglycan, with variants in multiple genes, including CRPPA, which is associated with a broad spectrum ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy.

The proband underwent whole exome sequencing, while Sanger sequencing was used for segregation analysis and oligonucleotide array-CGH was performed to confirm the copy number variant.

We report two siblings harboring an identical novel compound heterozygous CRPPA genotype, comprising a novel c.267G>C missense variant and a deletion encompassing exons 9-10. Despite sharing the same genotype, the siblings showed marked phenotypic variability. The female sibling developed childhood-onset disease with proximal weakness involving both the upper and lower limbs, whereas the male sibling presented with late-onset disease and weakness confined to the proximal lower limbs, accompanied by markedly discordant serum creatine kinase levels (1193 vs. 460 U/L).

These findings expand the mutational and clinical spectrum of CRPPA-related dystroglycanopathy, highlight marked intrafamilial phenotypic variability, and emphasize the importance of integrated single-nucleotide and copy number variant analysis in the genetic diagnosis of neuromuscular disorders.