Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease

Terry A Braun; Robert F Mullins; Alex H Wagner; Jeaneen L Andorf; Rebecca M Johnston; Benjamin B Bakall; Adam P Deluca; Gerald A Fishman; Byron L Lam; Richard G Weleber; Artur V Cideciyan; Samuel G Jacobson; Val C Sheffield; Budd A Tucker; Edwin M Stone

doi:10.1093/hmg/ddt367

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Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease

Journal article

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Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease

Terry A Braun, Robert F Mullins, Alex H Wagner, Jeaneen L Andorf, Rebecca M Johnston, Benjamin B Bakall, Adam P Deluca, Gerald A Fishman, Byron L Lam, Richard G Weleber, …

Human molecular genetics, Vol.22(25), pp.5136-5145

12/20/2013

DOI: 10.1093/hmg/ddt367

PMCID: PMC3842174

PMID: 23918662

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Abstract

Mutations in ABCA4 cause Stargardt disease and other blinding autosomal recessive retinal disorders. However, sequencing of the complete coding sequence in patients with clinical features of Stargardt disease sometimes fails to detect one or both mutations. For example, among 208 individuals with clear clinical evidence of ABCA4 disease ascertained at a single institution, 28 had only one disease-causing allele identified in the exons and splice junctions of the primary retinal transcript of the gene. Haplotype analysis of these 28 probands revealed 3 haplotypes shared among ten families, suggesting that 18 of the 28 missing alleles were rare enough to be present only once in the cohort. We hypothesized that mutations near rare alternate splice junctions in ABCA4 might cause disease by increasing the probability of mis-splicing at these sites. Next-generation sequencing of RNA extracted from human donor eyes revealed more than a dozen alternate exons that are occasionally incorporated into the ABCA4 transcript in normal human retina. We sequenced the genomic DNA containing 15 of these minor exons in the 28 one-allele subjects and observed five instances of two different variations in the splice signals of exon 36.1 that were not present in normal individuals (P < 10(-6)). Analysis of RNA obtained from the keratinocytes of patients with these mutations revealed the predicted alternate transcript. This study illustrates the utility of RNA sequence analysis of human donor tissue and patient-derived cell lines to identify mutations that would be undetectable by exome sequencing.

Haplotypes

Macular Degeneration - physiopathology

RNA Splice Sites - genetics

Alternative Splicing - genetics

Humans

Exons - genetics

Male

Exome - genetics

ATP-Binding Cassette Transporters - genetics

Macular Degeneration - genetics

Pedigree

Alleles

Aged, 80 and over

Adult

Female

Mutation

Retina - pathology

Details

Title: Subtitle: Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease
Creators: Terry A Braun - Department of Ophthalmology and Visual Sciences
Robert F Mullins
Alex H Wagner
Jeaneen L Andorf
Rebecca M Johnston
Benjamin B Bakall
Adam P Deluca
Gerald A Fishman
Byron L Lam
Richard G Weleber
Artur V Cideciyan
Samuel G Jacobson
Val C Sheffield
Budd A Tucker
Edwin M Stone
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.22(25), pp.5136-5145
DOI: 10.1093/hmg/ddt367
PMID: 23918662
PMCID: PMC3842174
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: DP2 OD007483 / NIH HHS R01 EY011298 / NEI NIH HHS T32 GM008629 / NIGMS NIH HHS
Language: English
Date published: 12/20/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Medical Genetics and Genomics; Center for Bioinformatics and Computational Biology; Ophthalmology and Visual Sciences
Record Identifier: 9983980058002771

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