Genetic etiology and clinical consequences of complete and incomplete achromatopsia.
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.


METHODS
Clinic-based, longitudinal, multicenter study.


METHODS
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.


METHODS
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.
Thiadens
Alberta A H J
AA
Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Slingerland
Niki W R
NW
Roosing
Susanne
S
van Schooneveld
Mary J
MJ
van Lith-Verhoeven
Janneke J C
JJ
van Moll-Ramirez
Norka
N
van den Born
L Ingeborgh
LI
Hoyng
Carel B
CB
Cremers
Frans P M
FP
Klaver
Caroline C W
CC
D000328:Adult; D055253:Color Vision / Q000502:physiology; D003117:Color Vision Defects / Q000235:genetics* / Q000503:physiopathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D015293:Transducin / Q000235:genetics; D014792:Visual Acuity / Q000502:physiology
C518238:CNGA3 protein, human; C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels; D015293:Transducin