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Genet Med. 2018 Oct 31. doi: 10.1038/s41436-018-0345-5. [Epub ahead of print]

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Author information

1
Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
2
Section of Ophthalmology and Neuroscience, School of Medicine, University of Leeds, St James's University Hospital, Leeds, UK.
3
Medical Genetics, Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
4
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
5
Genetics Department, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, Spain.
6
Center of Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
7
Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, Ghent, Belgium.
8
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
9
Department of Ophthalmology, St. James's University Hospital, Leeds, UK.
10
Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
11
Department of Ophthalmology, Fundación Jimenez Diaz University Hospital, Madrid, Spain.
12
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
13
Center for Medical Genetics, Antwerp University Hospital, Antwerp, Belgium.
14
Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
15
Medical Genetics, Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy. banfi@tigem.it.
16
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. banfi@tigem.it.
17
Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium. elfride.debaere@ugent.be.

Abstract

PURPOSE:

RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.

METHODS:

Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.

RESULTS:

Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.

CONCLUSION:

This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.

KEYWORDS:

RAX2; homeobox-containing transcription factor; loss of function; novel ARRP gene; retinitis pigmentosa

PMID:
30377383
DOI:
10.1038/s41436-018-0345-5

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