Dataset Information

Next-generation genetic testing for retinitis pigmentosa.

ABSTRACT: Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling.

SUBMITTER: Neveling K

PROVIDER: S-EPMC3490376 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Next-generation genetic testing for retinitis pigmentosa.

Neveling Kornelia K Collin Rob W J RW Gilissen Christian C van Huet Ramon A C RA Visser Linda L Kwint Michael P MP Gijsen Sabine J SJ Zonneveld Marijke N MN Wieskamp Nienke N de Ligt Joep J Siemiatkowska Anna M AM Hoefsloot Lies H LH Buckley Michael F MF Kellner Ulrich U Branham Kari E KE den Hollander Anneke I AI Hoischen Alexander A Hoyng Carel C Klevering B Jeroen BJ van den Born L Ingeborgh LI Veltman Joris A JA Cremers Frans P M FP Scheffer Hans H

Human mutation 20120319 6

Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and ...[more]

PMID: 22334370

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Project description:BACKGROUND:Retinitis pigmentosa (RP) is one of the major types of hereditary retinal dystrophies with extreme genotypic heterogeneity. To date, more than 80 genes have been identified to be associated with RP in human. METHOD:Here, we presented a clinical genetic study of three Chinese man manifested with night vision blindness and complete loss of midperipheral visual field. All of these three probands have been identified with loss of both central vision and far peripheral visual field. Gradual loss of rod cells followed by subsequent loss of cone cells have been identified in these probands. Targeted next generation sequencing and Sanger sequencing have been performed to understand the pathogenic variants underlying the disease phenotype in these three unrelated Chinese probands. RESULTS:Targeted next generation sequencing and Sanger sequencing identified three homozygous novel mutations (c.1880C>A; c.1459_1460delGA, and c.392G>A) in the MERTK gene in these three unrelated Chinese proband. In the first proband, the identified mutation (c.1880C>A) leads to the formation of a premature stop codon followed by the formation of a truncated mer-tyrosine kinase (MERTK) protein (p.Ser627*) product which predicted to be disease causing. In the second proband, the identified deletion (c.1459_1460delGA) leads to the formation of a frameshift which also finally results in the formation of a truncated MERTK protein (p.Asp487Leufs*57) product which also predicted to be disease causing. In the third proband, the identified mutation (c.392G>A) leads to the formation of a premature stop codon followed by the formation of a truncated MERTK protein (p.Trp131*) product which also predicted to be disease causing. Hence, these three mutations are loss-of-function mutations. These three mutations were absent in unaffected family members and in 100 normal healthy controls. CONCLUSION:Our present study also demonstrates the significance of targeted next generation sequencing in determining the genetic basis of RP.

Dataset Information

Next-generation genetic testing for retinitis pigmentosa.

Publications

Next-generation genetic testing for retinitis pigmentosa.

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