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Genet Med. 2014 Sep;16(9):671-80. doi: 10.1038/gim.2014.24. Epub 2014 Mar 13.

Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy.

Author information

1
Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
2
Department of Histology, Medical University of Sfax, Sfax, Tunisia.
3
Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
4
Department of Ophthalmology, Leuven University Hospitals, Leuven, Belgium.
5
Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium.
6
1] Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium [2] Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium [3] Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA [4] Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Abstract

PURPOSE:

Autosomal recessive retinal dystrophies are clinically and genetically heterogeneous, which hampers molecular diagnosis. We evaluated identity-by-descent-guided Sanger sequencing or whole-exome sequencing in 26 families with nonsyndromic (19) or syndromic (7) autosomal recessive retinal dystrophies to identify disease-causing mutations.

METHODS:

Patients underwent genome-wide identity-by-descent mapping followed by Sanger sequencing (16) or whole-exome sequencing (10). Whole-exome sequencing data were filtered against identity-by-descent regions and known retinal dystrophy genes. The medical history was reviewed in mutation-positive families.

RESULTS:

We identified mutations in 14 known retinal dystrophy genes in 20/26 (77%) families: ABCA4, CERKL, CLN3, CNNM4, C2orf71, IQCB1, LRAT, MERTK, NMNAT1, PCDH15, PDE6B, RDH12, RPGRIP1, and USH2A. Whole-exome sequencing in single individuals revealed mutations in either the largest or smaller identity-by-descent regions, and a compound heterozygous genotype in NMNAT1. Moreover, a novel deletion was found in PCDH15. In addition, we identified mutations in CLN3, CNNM4, and IQCB1 in patients initially diagnosed with nonsyndromic retinal dystrophies.

CONCLUSION:

Our study emphasized that identity-by-descent-guided mutation analysis and/or whole-exome sequencing are powerful tools for the molecular diagnosis of retinal dystrophy. Our approach uncovered unusual molecular findings and unmasked syndromic retinal dystrophies, guiding future medical management. Finally, elucidating ABCA4, LRAT, and MERTK mutations offers potential gene-specific therapeutic perspectives.

PMID:
24625443
DOI:
10.1038/gim.2014.24
[Indexed for MEDLINE]

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