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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease
Manon H C A Peeters1,2, Mubeen Khan1,2, Anoek A M B Rooijakkers1
1Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract:
Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the total 252 PRPH2 variants, more than half (n = 137) were missense variants. All variants were uploaded into the Leiden Open source Variation and ClinVar databases. Our study underscores the need for experimental assays for variants of unknown significance to improve pathogenicity classification, which would allow us to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.
Insights
Genetic mutations in PRPH2 cause inherited retinal diseases (IRDs). This study classified 252 PRPH2 variants, aiding understanding of genotype-phenotype correlations and future therapeutic strategies for IRDs.
Area of Science:
- Genetics
- Ophthalmology
Background:
- Mutations in the PRPH2 gene are linked to various inherited retinal diseases (IRDs).
- Numerous PRPH2 variants have been identified, but their causal roles require further elucidation.
Purpose of the Study:
- To systematically review and classify all published PRPH2 variants up to July 2020.
- To assess the pathogenicity of identified PRPH2 variants using established guidelines.
- To identify novel PRPH2 variants associated with IRDs.
Main Methods:
- Literature survey of PRPH2 variants in 720 index patients, identifying 245 unique variants.
- Identification of seven novel PRPH2 variants in eight additional patients.
- Application of the American College of Medical Genetics and Genomics (ACMG) guidelines for variant pathogenicity classification.
Main Results:
- A total of 252 PRPH2 variants were analyzed, including 245 previously reported and seven novel variants.
- 107 variants were classified as pathogenic and 92 as likely pathogenic.
- 50 variants remain of uncertain significance, highlighting the need for further functional studies.
Conclusions:
- The study provides a comprehensive classification of PRPH2 variants, contributing to the understanding of IRDs.
- Accurate pathogenicity classification is crucial for understanding genotype-phenotype correlations in PRPH2-associated IRDs.
- Further experimental validation of variants of uncertain significance is necessary to advance therapeutic strategies.
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