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

Frauke Coppieters (UGent) , Kristof Van Schil (UGent) , Miriam Bauwens (UGent) , Hannah Verdin (UGent) , Annelies De Jaegher (UGent) , Delfien Syx (UGent) , Tom Sante (UGent) , Steve Lefever (UGent) , Nouha Bouayed Abdelmoula, Fanny Depasse, et al.
(2014) GENETICS IN MEDICINE. 16(9). p.671-680
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Organization
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.
Keywords
IDENTIFICATION, REARRANGEMENTS, HOMOZYGOSITY, PCDH15 GENE, DISEASE GENES, identity-by-descent mapping, copy-number variation analysis, retinal dystrophy, variant filtering, whole-exome sequencing, LEBER CONGENITAL AMAUROSIS, CONE-ROD DYSTROPHY, RETINITIS-PIGMENTOSA, USHER-SYNDROME, AMELOGENESIS IMPERFECTA

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MLA
Coppieters, Frauke, et al. “Identity-by-Descent-Guided Mutation Analysis and Exome Sequencing in Consanguineous Families Reveals Unusual Clinical and Molecular Findings in Retinal Dystrophy.” GENETICS IN MEDICINE, vol. 16, no. 9, 2014, pp. 671–80, doi:10.1038/gim.2014.24.
APA
Coppieters, F., Van Schil, K., Bauwens, M., Verdin, H., De Jaegher, A., Syx, D., … De Baere, E. (2014). Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy. GENETICS IN MEDICINE, 16(9), 671–680. https://doi.org/10.1038/gim.2014.24
Chicago author-date
Coppieters, Frauke, Kristof Van Schil, Miriam Bauwens, Hannah Verdin, Annelies De Jaegher, Delfien Syx, Tom Sante, et al. 2014. “Identity-by-Descent-Guided Mutation Analysis and Exome Sequencing in Consanguineous Families Reveals Unusual Clinical and Molecular Findings in Retinal Dystrophy.” GENETICS IN MEDICINE 16 (9): 671–80. https://doi.org/10.1038/gim.2014.24.
Chicago author-date (all authors)
Coppieters, Frauke, Kristof Van Schil, Miriam Bauwens, Hannah Verdin, Annelies De Jaegher, Delfien Syx, Tom Sante, Steve Lefever, Nouha Bouayed Abdelmoula, Fanny Depasse, Ingele Casteels, Thomy de Ravel, Françoise Meire, Bart Leroy, and Elfride De Baere. 2014. “Identity-by-Descent-Guided Mutation Analysis and Exome Sequencing in Consanguineous Families Reveals Unusual Clinical and Molecular Findings in Retinal Dystrophy.” GENETICS IN MEDICINE 16 (9): 671–680. doi:10.1038/gim.2014.24.
Vancouver
1.
Coppieters F, Van Schil K, Bauwens M, Verdin H, De Jaegher A, Syx D, et al. Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy. GENETICS IN MEDICINE. 2014;16(9):671–80.
IEEE
[1]
F. Coppieters et al., “Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy,” GENETICS IN MEDICINE, vol. 16, no. 9, pp. 671–680, 2014.
@article{5696076,
  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.}},
  author       = {{Coppieters, Frauke and Van Schil, Kristof and Bauwens, Miriam and Verdin, Hannah and De Jaegher, Annelies and Syx, Delfien and Sante, Tom and Lefever, Steve and Abdelmoula, Nouha Bouayed and Depasse, Fanny and Casteels, Ingele and de Ravel, Thomy and Meire, Françoise and Leroy, Bart and De Baere, Elfride}},
  issn         = {{1098-3600}},
  journal      = {{GENETICS IN MEDICINE}},
  keywords     = {{IDENTIFICATION,REARRANGEMENTS,HOMOZYGOSITY,PCDH15 GENE,DISEASE GENES,identity-by-descent mapping,copy-number variation analysis,retinal dystrophy,variant filtering,whole-exome sequencing,LEBER CONGENITAL AMAUROSIS,CONE-ROD DYSTROPHY,RETINITIS-PIGMENTOSA,USHER-SYNDROME,AMELOGENESIS IMPERFECTA}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{671--680}},
  title        = {{Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy}},
  url          = {{http://dx.doi.org/10.1038/gim.2014.24}},
  volume       = {{16}},
  year         = {{2014}},
}

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