Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

By Raquel Perez-Carro, Marta Corton, Iker Sánchez-Navarro, Olga Zurita, Noelia Sanchez-Bolivar, Rocío Sánchez-Alcudia, Stefan H. Lelieveld, Elena Aller, Miguel Angel Lopez-Martinez, Mª Isabel López-Molina, Patricia Fernandez-San Jose, Fiona Blanco-Kelly, Rosa Riveiro-Alvarez, Christian Gilissen, Jose M Millan, Almudena Avila-Fernandez & Carmen Ayuso | Article number: 19531 | 2016

Abstract Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis.

Introduction Retinitis pigmentosa (RP, MIM 268000) is the most common form of inherited retinal degeneration with a prevalence of 1 in 4000 individuals. RP is characterized by primary rod degeneration leading to night blindness, the development of tunnel vision and slow progressive decrease in central vision. However, the disease onset, progression, retinal appearance and final visual outcome may vary significantly among patients, even within the same family. RP is also a highly heterogeneous genetic disorder; the disease can be inherited in different forms including autosomal dominant (adRP) in about 20-40% of the cases, autosomal recessive (arRP) in 30-50% or X-linked trait (xlRP) in 5-15% of the cases. Sporadic cases (sRP) account for about 40% of all diagnoses, although these percentages vary between different populations. Non-Mendelian inheritance patterns such as digenic, mitochondrial or de novo mutations have been also reported, though these account for a minor proportion of cases.

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