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Next‐generation genetic testing for retinitis pigmentosa
Author(s) -
Neveling Kornelia,
Collin Rob W.J.,
Gilissen Christian,
van Huet Ramon A.C.,
Visser Linda,
Kwint Michael P.,
Gijsen Sabine J.,
Zonneveld Marijke N.,
Wieskamp Nienke,
de Ligt Joep,
Siemiatkowska Anna M.,
Hoefsloot Lies H.,
Buckley Michael F.,
Kellner Ulrich,
Branham Kari E.,
den Hollander Anneke I.,
Hoischen Alexander,
Hoyng Carel,
Klevering B. Jeroen,
van den Born L. Ingeborgh,
Veltman Joris A.,
Cremers Frans P.M.,
Scheffer Hans
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22045
Subject(s) - retinitis pigmentosa , biology , abca4 , genetics , in silico , genetic testing , molecular diagnostics , genetic analysis , genetic heterogeneity , medical genetics , molecular genetics , mutation , indel , gene , genotype , single nucleotide polymorphism , phenotype
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. Hum Mutat 33:963–972, 2012. © 2012 Wiley Periodicals, Inc.