1. ¹Department of Ophthalmology, University Medical Centre Nijmegen, Nijmegen, The Netherlands
2. ²Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
3. ³The Rotterdam Eye Hospital, Rotterdam, The Netherlands
4. ⁴The Universitäts-Augenklinik, Ruprecht-Karls-Universität, Heidelberg, Germany
5. ⁵Department of Ophthalmology, Columbia University, New York, USA
6. ⁶Department of Pathology, Columbia University, New York, USA

Correspondence: Dr FPM Cremers, Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 24 3614017; fax: +31 24 3540488; E-mail: F.Cremers@antrg.umcn.nl

⁷These authors contributed equally to this study.

Received 18 February 2004; Revised 11 June 2004; Accepted 23 June 2004; Published online 20 October 2004.

Abstract

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone–rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone–rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod–cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.