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Genet Med. 2019 Jan 23. doi: 10.1038/s41436-018-0420-y. [Epub ahead of print]

ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.

Author information

1
Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
2
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Molecular Genetics Laboratory, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
6
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
7
Department of Computer Science, Free University of Brussels, Brussels, Belgium.
8
Department of Ophthalmology, Hôpital des Enfants Reine Fabiola, Brussels, Belgium.
9
Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
10
UK NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
11
UCL Institute of Ophthalmology, London, UK.
12
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
13
Center for Human Genetics, KU Leuven and UZ Leuven, Leuven, Belgium.
14
Centre de Génétique Humaine, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium.
15
GNOMIXX ltd, Statistics for Genomics, Melle, Belgium.
16
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
17
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
18
Division of Ophthalmology and Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
19
Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium. elfride.debaere@ugent.be.

Abstract

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.

KEYWORDS:

ABCA4-associated disease; AON; deep-intronic; missing heritability; noncoding

PMID:
30670881
DOI:
10.1038/s41436-018-0420-y

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