Frauke Coppieters1, Kristof Van Schil1, Miriam Bauwens1, Hannah Verdin1, Annelies De Jaegher1, Delfien Syx1, Tom Sante1, Steve Lefever1, Nouha Bouayed Abdelmoula2, Fanny Depasse3, Ingele Casteels4, Thomy de Ravel5, Françoise Meire3, Bart P Leroy6, Elfride De Baere1. 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.
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.
Authors: C Gerth-Kahlert; B Seebauer; S Dold; J V M Hanson; H Wildberger; A Spörri; H van Waes; W Berger Journal: Eye (Lond) Date: 2015-01-23 Impact factor: 3.775
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Authors: Scott H Greenwald; Jeremy R Charette; Magdalena Staniszewska; Lan Ying Shi; Steve D M Brown; Lisa Stone; Qin Liu; Wanda L Hicks; Gayle B Collin; Michael R Bowl; Mark P Krebs; Patsy M Nishina; Eric A Pierce Journal: Am J Pathol Date: 2016-05-18 Impact factor: 4.307
Authors: Kristof Van Schil; Françoise Meire; Marcus Karlstetter; Miriam Bauwens; Hannah Verdin; Frauke Coppieters; Eva Scheiffert; Christian Van Nechel; Thomas Langmann; Nicolas Deconinck; Elfride De Baere Journal: Genet Med Date: 2014-08-14 Impact factor: 8.822