Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa

被引:73
作者
Birtel, Johannes [1 ,2 ]
Gliem, Martin [1 ,2 ]
Mangold, Elisabeth [3 ]
Mueller, Philipp L. [1 ,2 ]
Holz, Frank G. [1 ,2 ]
Neuhaus, Christine [4 ]
Lenzner, Steffen [4 ]
Zahnleiter, Diana [4 ]
Betz, Christian [4 ]
Eisenberger, Tobias [4 ]
Bolz, Hanno J. [4 ,5 ]
Issa, Peter Charbel [1 ,2 ,6 ,7 ]
机构
[1] Univ Bonn, Dept Ophthalmol, Bonn, Germany
[2] Univ Bonn, Ctr Rare Dis Bonn ZSEB, Bonn, Germany
[3] Univ Bonn, Inst Human Genet, Bonn, Germany
[4] Bioscientia Ctr Human Genet, Ingelheim, Germany
[5] Univ Hosp Cologne, Inst Human Genet, Cologne, Germany
[6] Univ Oxford, Oxford Univ Hosp NHS Fdn Trust, Oxford Eye Hosp, Oxford, England
[7] Univ Oxford, Nuffield Lab Ophthalmol, Dept Clin Neurosci, Oxford, England
来源
PLOS ONE | 2018年 / 13卷 / 12期
关键词
LEBER CONGENITAL AMAUROSIS; COMPREHENSIVE MOLECULAR DIAGNOSIS; CONE-ROD DYSTROPHY; FUNDUS AUTOFLUORESCENCE; INCOMPLETE PENETRANCE; VISUAL FUNCTION; FREQUENT CAUSE; MUTATIONS; GENE; RPGR;
D O I
10.1371/journal.pone.0207958
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Retinitis pigmentosa (RP) is an inherited degenerative disease causing severe retinal dystrophy and visual impairment mainly with onset in infancy or adolescence. Targeted next-generation sequencing (NGS) has become an efficient tool to encounter the enormous genetic heterogeneity of diverse retinal dystrophies, including RP. To identify disease-causing mutations in unselected, consecutive RP patients, we conducted Sanger sequencing of genes commonly involved in the suspected genetic RP subtype, followed by targeted large-panel NGS if no mutation was identified, or NGS as primary analysis. A high (70%) detection rate of disease-causing mutations was achieved in a large cohort of 116 unrelated patients. About half (48%) of the solved RP cases were explained by mutations in four genes: RPGR, EYS, PRPF31 and USH2A. Overall, 110 different mutations distributed across 30 different genes were detected, and 46 of these mutations were novel. A molecular diagnosis was achieved in the majority (82-100%) of patients if the family history was suggestive for a particular mode of inheritance, but only in 60% in cases of sporadic RP. The diagnostic potential of extensive molecular analysis in a routine setting is also illustrated by the identification of unexpected genotype-phenotype correlations for RP patients with mutations in CRX, CEP290, RPGRIP1, MFSD8. Furthermore, we identified numerous mutations in autosomal dominant (PRPF31, PRPH2, CRX) and X-linked (RPGR) RP genes in patients with sporadic RP. Variants in RP2 and RPGR were also found in female RP patients with apparently sporadic or dominant disease. In summary, this study demonstrates that massively parallel sequencing of all known retinal dystrophy genes is a valuable diagnostic approach for RP patients.
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页数:18
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