Co-Existence of Novel PDE6A Mutations and A Recurrent RPGR Mutation: A Potential Explanation for Phenotypic Diversity...

To report the co-existence of novel biallelic PDE6A mutations and heterozygous RPGR mutation in a Chinese female patient with retinitis pigmentosa (RP), and to analyze the intrafamilial phenotypic diversity.

Three patients with retinopathy and four healthy family members were included in genetic and clinical analyses. Personal medical records were obtained from another four unaffected female family members who refused blood donation. Family history was carefully recorded. Each patient received comprehensive ophthalmic tests. Targeted next-generation sequencing (NGS) approach was performed on the proband to determine the retinopathy causative mutation for this family. In silico analysis was also applied to analyze the pathogenesis of identified mutations.

The two recruited male patients were diagnosed with RP, and the female patient RP sine pigmento (RPSP). Genetic assessments revealed a recurrent RPGR mutation, c.1926_1927insA, carried by all three patients and segregated the disease status. Three other unaffected female family members were confirmed as carriers for the identified RPGR mutation, and another four as obligate carriers. Interestingly, of all the eight female RPGR mutation carriers in this family, only one female developed retinal dystrophy. Comprehensive genetic analysis of this patient unraveled additional biallelic PDE6A mutations, c.[1066-9delT];[2324delG], carried solely by this individual.

Taken together, we hypothesize that the phenotypic variability presented by female RPGR mutation carriers may be attributed to the co-existence of other disease-causative mutations. Our study also emphasizes the importance of comprehensive genetic analysis in these female carriers, which will contribute to better diagnosis, prognosis, and treatment for these patients.