Journal
GENETICS IN MEDICINE
Volume 21, Issue 8, Pages 1761-1771Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-018-0420-y
Keywords
ABCA4-associated disease; missing heritability; non-coding; deep-intronic; AON
Categories
Funding
- Ghent University Special Research Fund [BOF15/GOA/011]
- Hercules Foundation [AUGE/13/023]
- Research Foundation Flanders [G0C6715N, G0A9718N]
- Foundation JED
- Funds for Research in Ophthalmology (FRO)
- FP7-PEOPLE-2012-ITN program EyeTN [317472]
- Foundation Fighting Blindness USA [PPA-0517-0717-RAD]
- Macula Vision Research Foundation
- Rotterdamse Stichting Blindenbelangen
- Stichting Blindenhulp
- Stichting tot Verbetering van het Lot der Blinden
- Landelijke Stichting voor Blinden en Slechtzienden
- Macula Degeneratie fonds
- Stichting Blinden-Penning
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Stichting Oogfonds Nederland
- Stichting Macula Degeneratie Fonds
- Stichting Retina Nederland Fonds
- Stichting voor Ooglijders
- Stichting Dowilvo
- National Institute for Health Research England (NIHR) [RG65966]
Ask authors/readers for more resources
Purpose: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. Methods: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. Results: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. Conclusion: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available