TY - JOUR
T1 - PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease
AU - Peeters, Manon H. C. A.
AU - Khan, Mubeen
AU - Rooijakkers, Anoek A. M. B.
AU - Mulders, Timo
AU - Haer-Wigman, Lonneke
AU - Boon, Camiel J. F.
AU - Klaver, Caroline C. W.
AU - van den Born, L. Ingeborgh
AU - Hoyng, Carel B.
AU - Cremers, Frans P. M.
AU - den Hollander, Anneke I.
AU - Dhaenens, Claire-Marie
AU - Collin, Rob W. J.
N1 - Funding Information: We gratefully acknowledge Stéphanie S. Cornelis for the assistance with the statistical analysis and LOVD submission, as well as Bjorn Bakker for technical assistance. Members of the study group (Drs. C. Ayuso; S. Banfi; T. Barakat; N. Bax; T. Ben‐Yosef, M. Breukink; J. de Hoog; J. de Roach; A. Delbecq; J. Ferraz Sallum; K. Fujinami; M. Gorin; W. Hartstra; Y. Hettinga; S. Ijzer; J. Keunen, A. Kievit; T. Kleefstra; T. Lamey; P. Liskova; M. Oldak; J. Ossewaarde ‐ van Norel; M. Phan; O. Podhajcer; P. Rump; M. Sinnema; D. Smailhodzic; C. Stumpel; A. Thiadens; J. van de Ven; R. van Leeuwen; S. Vermeer; J. Verheij and B. Weber) who submitted DNA samples in which variants were identified. This study was supported by an internal RadboudUMC PhD grant provided by the Donders Institute for Brain, Cognition and Behavior, as well as by the Foundation Fighting Blindness USA, grant BR‐GE‐0120‐0775‐LUMC. PRPH2 PRHP2 Funding Information: We gratefully acknowledge St?phanie S. Cornelis for the assistance with the statistical analysis and LOVD submission, as well as Bjorn Bakker for technical assistance. Members of the PRPH2 study group (Drs. C. Ayuso; S. Banfi; T. Barakat; N. Bax; T. Ben-Yosef, M. Breukink; J. de Hoog; J. de Roach; A. Delbecq; J. Ferraz Sallum; K. Fujinami; M. Gorin; W. Hartstra; Y. Hettinga; S. Ijzer; J. Keunen, A. Kievit; T. Kleefstra; T. Lamey; P. Liskova; M. Oldak; J. Ossewaarde - van Norel; M. Phan; O. Podhajcer; P. Rump; M. Sinnema; D. Smailhodzic; C. Stumpel; A. Thiadens; J. van de Ven; R. van Leeuwen; S. Vermeer; J. Verheij and B. Weber) who submitted DNA samples in which PRHP2 variants were identified. This study was supported by an internal RadboudUMC PhD grant provided by the Donders Institute for Brain, Cognition and Behavior, as well as by the Foundation Fighting Blindness USA, grant BR-GE-0120-0775-LUMC. Publisher Copyright: © 2021 The Authors. Human Mutation published Wiley Periodicals LLC
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - LOVD
KW - PRPH2
KW - in silico assessment
KW - inherited retinal disease
KW - molecular genetics
UR - http://www.scopus.com/inward/record.url?scp=85115130633&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/humu.24275
DO - https://doi.org/10.1002/humu.24275
M3 - Article
C2 - 34411390
SN - 1059-7794
VL - 42
SP - 1521
EP - 1547
JO - Human mutation
JF - Human mutation
IS - 12
ER -