Genetic etiology and clinical consequences of complete and incomplete achromatopsia

Alberta A H J Thiadens; Niki W R Slingerland; Susanne Roosing; Mary J van Schooneveld; Janneke J C van Lith-Verhoeven; Norka van Moll-Ramirez; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Caroline C W Klaver

doi:10.1016/j.ophtha.2009.03.053

Genetic etiology and clinical consequences of complete and incomplete achromatopsia

Alberta A H J Thiadens, Niki W R Slingerland, Susanne Roosing, Mary J van Schooneveld, Janneke J C van Lith-Verhoeven, Norka van Moll-Ramirez, L Ingeborgh van den Born, Carel B Hoyng, Frans P M Cremers, Caroline C W Klaver

Medical retina and Uveitis

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	1984-9.e1
Journal	Ophthalmology
Volume	116
Issue number	10
DOIs	https://doi.org/10.1016/j.ophtha.2009.03.053
Publication status	Published - Oct 2009

Keywords

Adult
Color Vision/physiology
Color Vision Defects/genetics
Cyclic Nucleotide-Gated Cation Channels/genetics
DNA Mutational Analysis
Female
Follow-Up Studies
Genotype
Humans
Male
Mutation
Phenotype
Polymerase Chain Reaction
Retinal Cone Photoreceptor Cells/physiology
Retinal Degeneration/genetics
Transducin/genetics
Visual Acuity/physiology

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10.1016/j.ophtha.2009.03.053

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Thiadens, A. A. H. J., Slingerland, N. W. R., Roosing, S., van Schooneveld, M. J., van Lith-Verhoeven, J. J. C., van Moll-Ramirez, N., van den Born, L. I., Hoyng, C. B., Cremers, F. P. M., & Klaver, C. C. W. (2009). Genetic etiology and clinical consequences of complete and incomplete achromatopsia. Ophthalmology, 116(10), 1984-9.e1. https://doi.org/10.1016/j.ophtha.2009.03.053

@article{c6461a4c1b20433cb03e33907a97e4c4,

title = "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.",

keywords = "Adult, Color Vision/physiology, Color Vision Defects/genetics, Cyclic Nucleotide-Gated Cation Channels/genetics, DNA Mutational Analysis, Female, Follow-Up Studies, Genotype, Humans, Male, Mutation, Phenotype, Polymerase Chain Reaction, Retinal Cone Photoreceptor Cells/physiology, Retinal Degeneration/genetics, Transducin/genetics, Visual Acuity/physiology",

author = "Thiadens, {Alberta A H J} and Slingerland, {Niki W R} and Susanne Roosing and {van Schooneveld}, {Mary J} and {van Lith-Verhoeven}, {Janneke J C} and {van Moll-Ramirez}, Norka and {van den Born}, {L Ingeborgh} and Hoyng, {Carel B} and Cremers, {Frans P M} and Klaver, {Caroline C W}",

year = "2009",

month = oct,

doi = "10.1016/j.ophtha.2009.03.053",

language = "English",

volume = "116",

pages = "1984--9.e1",

number = "10",

}

TY - JOUR

T1 - Genetic etiology and clinical consequences of complete and incomplete achromatopsia

AU - Thiadens, Alberta A H J

AU - Slingerland, Niki W R

AU - Roosing, Susanne

AU - van Schooneveld, Mary J

AU - van Lith-Verhoeven, Janneke J C

AU - van Moll-Ramirez, Norka

AU - van den Born, L Ingeborgh

AU - Hoyng, Carel B

AU - Cremers, Frans P M

AU - Klaver, Caroline C W

PY - 2009/10

Y1 - 2009/10

N2 - 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.

AB - 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.

KW - Adult

KW - Color Vision/physiology

KW - Color Vision Defects/genetics

KW - Cyclic Nucleotide-Gated Cation Channels/genetics

KW - DNA Mutational Analysis

KW - Female

KW - Follow-Up Studies

KW - Genotype

KW - Humans

KW - Male

KW - Mutation

KW - Phenotype

KW - Polymerase Chain Reaction

KW - Retinal Cone Photoreceptor Cells/physiology

KW - Retinal Degeneration/genetics

KW - Transducin/genetics

KW - Visual Acuity/physiology

U2 - 10.1016/j.ophtha.2009.03.053

DO - 10.1016/j.ophtha.2009.03.053

M3 - Article

C2 - 19592100

SN - 0161-6420

VL - 116

SP - 1984-9.e1

JO - Ophthalmology

JF - Ophthalmology

IS - 10

ER -

Genetic etiology and clinical consequences of complete and incomplete achromatopsia

Abstract

Keywords

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