Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone...

Area of Science:

• Ophthalmology and Genetics
• Molecular Biology
• Nephrology

Background:

• Rod-cone dystrophy (RCD) is a group of inherited retinal diseases.
• Genetic mutations are often implicated in RCD and related syndromic conditions.
• Joubert and Meckel-Gruber syndromes are typically associated with CC2D2A mutations.

Purpose of the Study:

• To investigate the genetic basis of complex phenotypes including RCD and nephrotic-range proteinuria in a consanguineous family.
• To identify causative genetic variants using advanced sequencing techniques.
• To explore the role of CC2D2A and other genes in isolated retinal dystrophies.

Main Methods:

• Genetic analysis including targeted next-generation sequencing and whole exome sequencing (WES) was performed on affected siblings and family members.
• Analysis of identified variants in relation to clinical phenotypes.
• Comparison of identified variants with known disease-associated genes and databases.

Main Results:

• Whole exome sequencing identified compound heterozygous variants in CC2D2A in all three brothers.
• A homozygous deletion in CNGA3 was found in the youngest brother, leading to a revised diagnosis of achromatopsia plus RCD.
• Compound heterozygous variants in CUBN were identified in the two youngest brothers, potentially explaining their nephrotic-range proteinuria.

Conclusions:

• This study reports, for the first time, CC2D2A mutations associated with isolated rod-cone dystrophy, expanding the known phenotypic spectrum of this gene.
• Whole exome sequencing proved effective in diagnosing complex genetic disorders with overlapping or atypical presentations.
• The findings highlight the genetic heterogeneity of retinal dystrophies and the importance of comprehensive genetic analysis.