Phenotype/genotype correlation in a case series of Stargardt's patients identifies novel mutations in the ABCA4 gene

Eye (2013) 27, 13161319 & 2013 Macmillan Publishers Limited All rights reserved 0950-222X/13

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M Gemenetzi1 and AJ Lotery1,2

CASESERIES

Phenotype /genotype correlation in a case series of Stargardts patients identies novel mutationsin the ABCA4 gene

1Southampton Eye Unit, Southampton General Hospital, Southampton, UK

2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

Correspondence:AJ Lotery, South Lab and Path Block, Mailpoint 806, Level D, University Hospital Southampton, Southampton SO16 6YD, UK.

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This work was previously presented in ARVO, 610 May 2012.

Received: 14 May 2013 Accepted in revised form:16 July 2013Published online: 16 August 2013

Abstract

Purpose To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and conrmed ABCA4 mutations.

Methods Entire coding region analysisof the ABCA4 gene by direct sequencingof seven patients with clinical ndingsof STGD seen in the Retina Clinics of Southampton Eye Unit between 2002and 2011.

Phenotypic variables recorded were BCVA, uorescein angiographic appearance, electrophysiology, and visual elds.

Results All patients had heterozygous amino acid-changing variants(missense mutations) in the ABCA4 gene.

A splice sequence change was foundin a 30-year-old patient with severly affected vision. Two novel sequence changes were identied: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient.

Conclusion The identied ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA.

Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype.

This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information

may prove useful in selection of candidates for clinical trials in ABCA4 disease.

Eye (2013) 27, 13161319; doi:http://dx.doi.org/10.1038/eye.2013.176

Web End =10.1038/eye.2013.176 ; published online 16 August 2013

Keywords: Stargardt disease; fundus avimaculatus; cone-rod dystrophy; ABCA4 gene mutations

Introduction

The ABCA4 gene produces an ATP-binding cassette superfamily transmembrane protein expressed in retinal photoreceptors and involved in the transport of substrates across membranes. It is a large gene consisting of 50 exons. Missense mutations in this gene were rst identied as causing Stargardt disease (STGD)...