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Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign.

ABSTRACT: Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced.Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy.Rates of rare (minor allele frequency ?0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not.We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation.

SUBMITTER: Strom SP

PROVIDER: S-EPMC3654847 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign.

Strom Samuel P SP Gorin Michael B MB

Molecular vision 20130506

<h4>Background</h4>Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced.<h4>Methods</h4>Publicly available data from the Exome Variant Project were analyzed, f ...[more]

PMID: 23687434

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Project description:ImportanceThe patients evaluated in this study, to our knowledge, represent the first complete clinical description of a family with an autosomal dominant inheritance pattern of retinal dystrophy associated with a novel mutation in RAX2.ObjectivesTo clinically evaluate 4 patients and 5 unaffected family members, characterize the disease phenotype over time, and identify the associated genetic mutation.Design, setting, and participantsA prospective, longitudinal, observational, case-series analysis of 9 members of an affected family at the Casey Eye Institute, Oregon Health and Science University, Portland. The dates of the study were from July 31, 1992, to August 11, 2014.InterventionsClinical evaluations included eye examination, color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography, kinetic visual field testing, and electroretinography. Genetic mutation screening was performed with next-generation sequencing, and identified mutations were confirmed with Sanger sequencing.Main outcomes and measuresClinical diagnosis and longitudinal characterization of retinal dystrophy and identification of genetic mutation.ResultsSix members of the family were identified as having retinal dystrophy (4 were examined, and 3 were genetically tested). Five unaffected family members were clinically evaluated (2 were genetically tested). The age at onset of retinal dystrophy was variable. All affected individuals presented with declining visual acuity, central scotomas, waxy disc pallor, attenuated vasculature, small yellow macular deposits and/or macular pigment mottling, and abnormal electroretinograms demonstrating mixed cone and rod dysfunction and a scotopic electronegative response to bright flashes. There were no other causes of an electronegative electroretinogram identified in any of the affected patients. Genetic testing revealed, to our knowledge, a novel frameshift heterozygous mutation in RAX2 in the patients with retinal dystrophy.Conclusions and relevanceA frameshift heterozygous mutation in RAX2 inherited in an autosomal dominant fashion was associated with mixed cone and rod dysfunction. Among the patients, there was variability in the age at onset and in the specific pattern of photoreceptor dysfunction, but the clinical course was nevertheless slowly progressive. Screening for RAX2 mutation could provide prognostic value for patients and families with scotopic electronegative responses to bright flashes.

Dataset Information

Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign.

Publications

Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign.

Similar Datasets

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