Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes

被引:20
|
作者
Astuti, Galuh D. N. [1 ,2 ]
van den Born, L. Ingeborgh [3 ]
Khan, M. Imran [1 ,4 ]
Hamel, Christian P. [5 ,6 ,7 ]
Bocquet, Beatrice [5 ,6 ,7 ]
Manes, Gael [5 ,6 ]
Quinodoz, Mathieu [8 ]
Ali, Manir [9 ]
Toomes, Carmel [9 ]
McKibbin, Martin [10 ]
El-Asrag, Mohammed E. [9 ,11 ]
Haer-Wigman, Lonneke [1 ]
Inglehearn, Chris F. [9 ]
Black, Graeme C. M. [12 ]
Hoyng, Carel B. [13 ]
Cremers, Frans P. M. [1 ,4 ]
Roosing, Susanne [1 ,4 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, NL-6525 GA Nijmegen, Netherlands
[3] Rotterdam Eye Hosp, NL-3011 BH Rotterdam, Netherlands
[4] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands
[5] Inst Neurosci Montpellier, Inst Natl Sante & Rech Med, F-34080 Montpellier, France
[6] Univ Montpellier, F-34090 Montpellier, France
[7] CHRU, Genet Sensory Dis, F-34295 Montpellier, France
[8] Univ Lausanne, Dept Computat Biol, Unit Med Genet, CH-1015 Lausanne, Switzerland
[9] Univ Leeds, St Jamess Univ Hosp, Leeds Inst Biomed & Clin Sci, Sect Ophthalmol & Neurosci, Leeds LS9 7TF, W Yorkshire, England
[10] St James Univ Hosp, Dept Ophthalmol, Leeds LS9 7TF, W Yorkshire, England
[11] Benha Univ, Fac Sci, Dept Zool, Banha 13511, Egypt
[12] Univ Manchester, St Marys Hosp, Ctr Genom Med, Manchester Acad Hlth Sci Ctr, Manchester M13 9PL, Lancs, England
[13] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 EX Nijmegen, Netherlands
来源
GENES | 2018年 / 9卷 / 01期
基金
瑞士国家科学基金会;
关键词
whole exome sequencing; inherited retinal diseases; candidate retinal disease genes; LEBER CONGENITAL AMAUROSIS; RETINITIS-PIGMENTOSA; OTOGELIN-LIKE; MUTATIONS; PROTEIN; HETEROGENEITY; BLINDNESS; IDENTIFY; THERAPY; RPE65;
D O I
10.3390/genes9010021
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies <= 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.
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页数:16
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