Pathogenicity discrimination and genetic test reference for CRX variants based on genotype-phenotype analysis.

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• The cone-rod homeobox (CRX) gene is crucial for photoreceptor development and function.
• Previously, rare CRX variants were often presumed causative for retinal degeneration, but this assumption requires re-evaluation.
• Limited genetic diversity in CRX coding regions complicates variant interpretation.

Purpose of the Study:

• To classify CRX variants using genotype-phenotype analysis in Chinese families and literature data.
• To reassess the pathogenicity of known and novel CRX variants.
• To provide critical information for clinical genetic testing of CRX and other genes.

Main Methods:

• Exome sequencing of 4971 Chinese probands with eye diseases.
• Detection of 24 CRX variants in 37 families, including 14 novel ones.
• Genotype-phenotype correlation, cosegregation analysis, and literature review.

Main Results:

• Classified 24 CRX variants into benign (6), likely benign (6), and pathogenic (12) groups.
• Identified somatic mosaicism in a family with unaffected parents and affected children.
• Found that approximately half of heterozygous missense variants and some truncating variants are likely benign; truncating mutations after the homeodomain correlate with severe phenotypes.

Conclusions:

• Many rare CRX missense and some truncating variants are likely benign, contrary to some computational predictions.
• Variant nature and location are critical for determining pathogenicity.
• This genotype-phenotype reassessment is vital for accurate genetic diagnosis of retinal diseases.