Mutation spectrum of the ABCA4 gene in 335 stargardt disease patients from a multicenter German cohort—impact of selected deep intronic variants and common SNPs

Heidi L. Schulz, Felix Grassmann, Ulrich Kellner, Georg Spital, Klaus Rüther, Herbert Jägle, Karsten Hufendiek, Philipp Rating, Cord Huchzermeyer, Maria J. Baier, Bernhard H.F. Weber, Heidi Stöhr*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)


PURPOSE. Stargardt disease (STGD1) is an autosomal recessive retinopathy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene. To establish the mutational spectrum and to assess effects of selected deep intronic and common genetic variants on disease, we performed a comprehensive sequence analysis in a large cohort of German STGD1 patients. METHODS. DNA samples of 335 STGD1 patients were analyzed for ABCA4 mutations in its 50 coding exons and adjacent intronic sequences by resequencing array technology or next generation sequencing (NGS). Parts of intron 30 and 36 were screened by Sanger chainterminating dideoxynucleotide sequencing. An in vitro splicing assay was used to test selected variants for their splicing behavior. By logistic regression analysis we assessed the association of common ABCA4 alleles while a multivariate logistic regression model calculated a genetic risk score (GRS). RESULTS. Our analysis identified 148 pathogenic or likely pathogenic mutations, of which 48 constitute so far unpublished ABCA4-associated disease alleles. Four rare deep intronic variants were found once in 472 alleles analyzed. In addition, we identified six risk-modulating common variants. Genetic risk score estimates suggest that defined common ABCA4 variants influence disease risk in carriers of a single pathogenic ABCA4 allele. CONCLUSIONS. Our study adds to the mutational spectrum of the ABCA4 gene. Moreover, in our cohort, deep intronic variants in intron 30 and 36 likely play no or only a minor role in disease pathology. Of note, our findings demonstrate a possible modifying effect of common sequence variants on ABCA4-associated disease.

Original languageEnglish
Pages (from-to)394-403
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Issue number1
Early online date29 Nov 2016
Publication statusPublished - Jan 2017

Bibliographical note

The authors thank the International AMD Genomics Consortium (IAMDGC, for providing the genotypes in the ABCA4 gene for our control samples. They also thank Jennifer Loewen-Horsch and Romy Walker for their help with the in vitro splicing assays and intronic sequencing. Supported in part by grants from the ProRetina Foundation
Germany and the Federal Ministry of Education and Research (BMBF) (Ref. IDs 01GM0851 and 01GM1108B). The samples were genotyped as part of the IAMDGC exome-chip project supported by CIDR contract HHSN268201200008I and funded by EY022310 (to Jonathan L. Haines) and 1X01HG006934-01 (to Goncalo R. Abecasis)


  • ABCA4
  • Genetic risk score
  • Mutation screening
  • Stargardt disease


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