Genetic Etiology and Clinical Consequences of Complete and Incomplete Achromatopsia

Abstract

Purpose: : To investigate the genetic causes of complete and incomplete achromatopsia (ACHM), and to assess the association between disease-causing mutations, phenotype at diagnosis, and visual prognosis.

Methods: : The ophthalmologic clinical data of probands with complete ACHM (N=47), incomplete ACHM (N=32) and their affected relatives (N=18), were registered from medical charts and updated by ophthalmologic examination. Mutations in the CNGB3, CNGA3, and GNAT2 gene were analyzed by direct sequencing.

Results: : Five CNGB3 mutations were identified in 55/63 (87%) of patients; the most common mutation was p.T383IfsX13 (80%). We also detected a novel frameshift mutation p.G548VfsX35. CNGA3 mutations were detected in 3/63 (5%) probands, and no mutations were found in the GNAT2 gene. ACHM subtype, visual acuity, color vision, refractive error, and macular appearance were equally distributed among the CNGB3 genotypes, but appeared to be slightly worse among CNGA3 genotypes. Visual acuity deteriorated from infancy to adulthood in 12% of patients, leading to 20/200 in 61%, and even lower than 20/200 in 20% of patients.

Conclusions: : In this well-defined cohort of ACHM patients, the disease appeared much more genetically homogeneous than previously described. The CNGB3 gene was by far the most important causal gene, and T383IfsX13 the most frequent mutation. ACHM subtype did not associate with a distinct genetic etiology, nor were any other genotype-phenotype correlations significant. The distinction between complete and incomplete subtypes of ACHM has no clinical value, and the assumption of a stationary nature is misleading.

Keywords: gene/expression • mutations • retina