PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Inherited retinal dystrophies (IRDs) encompass a heterogeneous group of disorders affecting photoreceptor cells.
• Mutations in the retinol dehydrogenase 12 (RDH12) gene are a known cause of IRDs, particularly early-onset severe forms.
• Understanding the spectrum of RDH12 mutations and their associated phenotypes is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To identify and characterize genetic defects in the RDH12 gene in a cohort of Chinese patients with inherited retinal dystrophies.
• To delineate the phenotypic variability associated with biallelic RDH12 variants.
• To investigate the frequency and spectrum of RDH12 mutations in this population.

Main Methods:

• Genetic analysis of 38 unrelated families using next-generation sequencing and Sanger sequencing.
• Segregation analysis to confirm pathogenicity of identified variants.
• Comprehensive ophthalmic examinations including electroretinography, fundus imaging, and optical coherence tomography to assess phenotype.

Main Results:

• Twenty-five distinct RDH12 mutations were identified, including six novel variants.
• High-frequency mutations such as Val146Asp, Arg62Ter, and Thr49Met were observed.
• The majority of patients presented with early-onset severe retinal dystrophy, Leber congenital amaurosis, or autosomal recessive retinitis pigmentosa; cone-rod dystrophy was rare.
• Nyctalopia was prevalent, particularly in older patients, and correlated with disease progression.

Conclusions:

• Biallelic RDH12 mutations are a significant genetic cause of early-onset retinal dystrophies in the Chinese population.
• The study identified common and novel RDH12 variants, highlighting missense mutations as frequent.
• Phenotypic presentation is variable but progressive, emphasizing the importance of RDH12 genetic testing for diagnosing retinal dystrophies.