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.
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.
Authors: Jonathan P Greenberg; Jerome Sherman; Sandrine A Zweifel; Royce W S Chen; Tobias Duncker; Susanne Kohl; Britta Baumann; Bernd Wissinger; Lawrence A Yannuzzi; Stephen H Tsang Journal: JAMA Ophthalmol Date: 2014-04-01 Impact factor: 7.389
Authors: I A Viringipurampeer; X Shan; K Gregory-Evans; J P Zhang; Z Mohammadi; C Y Gregory-Evans Journal: Cell Death Differ Date: 2014-01-10 Impact factor: 15.828
Authors: Anna M Siemiatkowska; Rob W J Collin; Anneke I den Hollander; Frans P M Cremers Journal: Cold Spring Harb Perspect Med Date: 2014-06-17 Impact factor: 6.915
Authors: Maleeha Azam; Rob W J Collin; Syed Tahir Abbas Shah; Aftab Ali Shah; Muhammad Imran Khan; Alamdar Hussain; Ahmed Sadeque; Tim M Strom; Alberta A H J Thiadens; Susanne Roosing; Anneke I den Hollander; Frans P M Cremers; Raheel Qamar Journal: Mol Vis Date: 2010-04-29 Impact factor: 2.367
Authors: Alberta A H J Thiadens; Anneke I den Hollander; Susanne Roosing; Sander B Nabuurs; Renate C Zekveld-Vroon; Rob W J Collin; Elfride De Baere; Robert K Koenekoop; Mary J van Schooneveld; Tim M Strom; Janneke J C van Lith-Verhoeven; Andrew J Lotery; Norka van Moll-Ramirez; Bart P Leroy; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Caroline C W Klaver Journal: Am J Hum Genet Date: 2009-07-16 Impact factor: 11.025