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Genetic etiology and clinical consequences of complete and incomplete achromatopsia.

Abstract：

OBJECTIVE:To investigate the genetic causes of complete and incomplete achromatopsia (ACHM) and assess the association between disease-causing mutations, phenotype at diagnosis, and visual prognosis. DESIGN:Clinic-based, longitudinal, multicenter study. PARTICIPANTS:Probands with complete ACHM (n = 35), incomplete ACHM (n = 26), or nonspecific ACHM (n = 2) and their affected relatives (n = 18) from various ophthalmogenetic clinics in The Netherlands. METHODS:Ophthalmologic clinical data were assessed over a life time and were registered from medical charts and updated by ophthalmologic examination. Mutations in the CNGB3, CNGA3, and GNAT2 genes were analyzed by direct sequencing. MAIN OUTCOME MEASURES:Genetic mutations and clinical course of ACHM. RESULTS:CNGB3 mutations were identified in 55 of 63 (87%) of probands and all caused premature truncation of the protein. The most common mutation was p.T383IfsX13 (80%); among the 4 other mutations was the novel frameshift mutation p.G548VfsX35. CNGA3 mutations were detected in 3 of 63 (5%) probands; all caused an amino acid change of the protein. No mutations were found in the GNAT2 gene. The ACHM subtype, visual acuity, color vision, and macular appearance were equally distributed among the CNGB3 genotypes, but were more severely affected among CNGA3 genotypes. Visual acuity deteriorated from infancy to adulthood in 12% of patients, leading to 0.10 in 61%, and even lower than 0.10 in 20% of patients. CONCLUSIONS:In this well-defined cohort of ACHM patients, the disease seemed much more genetically homogeneous than previously described. The CNGB3 gene was by far the most important causal gene, and T383IfsX13 the most frequent mutation. The ACHM subtype did not associate with a distinct genetic etiology, nor were any other genotype-phenotype correlations apparent. The distinction between complete and incomplete subtypes of ACHM has no clinical value, and the assumption of a stationary nature is misleading.

journal_name

Ophthalmology

journal_title

Ophthalmology

authors

Thiadens AA,Slingerland NW,Roosing S,van Schooneveld MJ,van Lith-Verhoeven JJ,van Moll-Ramirez N,van den Born LI,Hoyng CB,Cremers FP,Klaver CC

doi

10.1016/j.ophtha.2009.03.053

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

1984-9.e1

issue

eissn

0161-6420

issn

1549-4713

pii

S0161-6420(09)00350-9

journal_volume

116

pub_type

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Genetic etiology and clinical consequences of complete and incomplete achromatopsia.