NDLI: Analysis of the ABCA4 genomic locus in Stargardt disease

Content Provider	PubMed Central
Author	Jana, Zernant Xie, Yajing (angela) Ayuso, Carmen Rosa, Riveiro-alvarez Lopez-martinez, Miguel-angel Simonelli, Francesca Testa, Francesco Gorin, Michael B. Strom, Samuel P. Bertelsen, Mette Rosenberg, Thomas Boone, Philip M. Yuan, Bo Radha, Ayyagari Nagy, Peter L. Tsang, Stephen H. Gouras, Peter Collison, Frederick T. Lupski, James R. Fishman, Gerald A. Rando, Allikmets Xie, Yajing
Copyright Year	2014
Abstract	Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65–70% of patients and only one mutation in 15–20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.
Related Links	http://dx.doi.org/10.1093/hmg/ddu396
Ending Page	6806
Page Count	10
Starting Page	6797
File Format	PDF
ISSN	09646906
e-ISSN	14602083
Journal	Human Molecular Genetics
Issue Number	25
Volume Number	23
Language	English
Publisher	Oxford University Press
Publisher Date	2014-12-20
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Genetics(clinical) Genetics Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Genetics (clinical)

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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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