NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene
Abstract
:1. Introduction
2. Materials and Methods
2.1. Clinical Details
2.2. Laboratory Investigations
2.3. Variant Interpretation
3. Results and Discussion
- it is not described in the main databases (GnomAD, ExAc and 1000 Genomes) reporting variants frequency in the general population;
- it is located in a gene with a low rate of benign missense variations;
- multiple bioinformatic tools reported c.668T > A as a disease-causing variant;
- it has not been found in more than 100 control tested subjects;
- patient’s phenotype or family history is highly specific for a disease with a single genetic etiology;
- it has been detected in another affected family member;
Author Contributions
Funding
Conflicts of Interest
References
- Cascella, R.; Strafella, C.; Germani, C.; Novelli, G.; Ricci, F.; Zampatti, S.; Giardina, E. The Genetics and the Genomics of Primary Congenital Glaucoma. Biomed. Res. Int. 2015, 2015, 321291. [Google Scholar] [CrossRef] [PubMed]
- Verbakel, S.K.; van Huet, R.A.C.; Boon, C.J.F.; den Hollander, A.I.; Collin, R.W.J.; Klaver, C.C.W.; Hoyng, C.B.; Roepman, R.; Klevering, B.J. Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 2018, 66, 157–186. [Google Scholar] [CrossRef] [PubMed]
- Cascella, R.; Strafella, C.; Longo, G.; Ragazzo, M.; Manzo, L.; De Felici, C.; Errichiello, V.; Caputo, V.; Viola, F.; Eandi, C.M.; et al. Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants. Oncotarget 2017, 9, 7812–7821. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ali, M.U.; Rahman, M.S.U.; Cao, J. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario. 3Biotech 2017, 7, 251. [Google Scholar] [CrossRef]
- Fiorentino, A.; Yu, J.; Arno, G.; Pontikos, N.; Halford, S.; Broadgate, S.; Michaelides, M.; Carss, K.J.; Raymond, F.L.; Cheetham, M.E.; et al. Novel homozygous splicing mutations in ARL2BP cause autosomal recessive retinitis pigmentosa. Mol. Vis. 2018, 24, 603–612. [Google Scholar]
- Dias, M.F.; Joo, K.; Kemp, J.A.; Fialho, S.L.; da Silva Cunha, A., Jr.; Woo, S.J.; Kwon, Y.J. Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives. Prog. Retin. Eye Res. 2018, 63, 107–131. [Google Scholar] [CrossRef]
- Birtel, J.; Gliem, M.; Mangold, E.; Müller, P.L.; Holz, F.G.; Neuhaus, C.; Lenzner, S.; Zahnleiter, D.; Betz, C.; Eisenberger, T.; et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS ONE 2018, 13, e0207958. [Google Scholar] [CrossRef]
- Adams, D.R.; Eng, C.M. Next-generation sequencing to diagnose suspected genetic disorders. N. Engl. J. Med. 2019, 379, 1353–1362. [Google Scholar] [CrossRef]
- Strafella, C.; Campoli, G.; Galota, R.M.; Caputo, V.; Pagliaroli, G.; Carboni, S.; Zampatti, S.; Peconi, C.; Mela, J.; Sancricca, C.; et al. Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report. Front Neurol. 2019, 10, 619. [Google Scholar] [CrossRef] [Green Version]
- Schwarz, J.M.; Cooper, D.N.; Schuelke, M.; Seelow, D. MutationTaster2: Mutation prediction for the deep-sequencing age. Nat. Methods 2014, 11, 361–362. [Google Scholar] [CrossRef]
- Sim, N.L.; Kumar, P.; Hu, J.; Henikoff, S.; Schneider, G.; Ng, P.C. SIFT web server: Predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012, 40, W452–W457. [Google Scholar] [CrossRef]
- Adzhubei, I.; Jordan, D.M.; Sunyaev, S.R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. 2013, 76, 7–20. [Google Scholar] [CrossRef]
- Desmet, F.O.; Hamroun, D.; Lalande, M.; Collod-Béroud, G.; Claustres, M.; Béroud, C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009, 37, e67. [Google Scholar] [CrossRef] [PubMed]
- Kopanos, C.; Tsiolkas, V.; Kouris, A.; Chapple, C.E.; Albarca Aguilera, M.; Meyer, R.; Massouras, A. VarSome: The Human Genomic Variant Search Engine. Bioinformatics 2018, 35, 1978–1980. [Google Scholar] [CrossRef] [PubMed]
- Kelley, L.A.; Mezulis, S.; Yates, C.M.; Wass, M.N.; Sternberg, M.J. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 2015, 10, 845–858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- PDBsum: Pictorial database of 3D structures in the Protein Data Bank. Available online: https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/DisaStr/GetPage.pl?uniprot_acc=n/a&template=home.html (accessed on 18 July 2019).
- Ittisoponpisan, S.; Islam, S.A.; Khanna, T.; Alhuzimi, E.; David, A.; Sternberg, M.J.E. Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated? J. Mol. Biol. 2019, 431, 2197–2212. [Google Scholar] [CrossRef]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef]
- Manes, G.; Guillaumie, T.; Vos, W.L.; Devos, A.; Audo, I.; Zeitz, C.; Marquette, V.; Zanlonghi, X.; Defoort-Dhellemmes, S.; Puech, B.; et al. High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features. Am. J. Ophthalmol. 2015, 159, 302–314. [Google Scholar] [CrossRef]
- Boon, C.J.; den Hollander, A.I.; Hoyng, C.B.; Cremers, F.P.; Klevering, B.J.; Keunen, J.E. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog. Retin. Eye Res. 2008, 27, 213–235. [Google Scholar] [CrossRef]
- Chakraborty, D.; Rodgers, K.K.; Conley, S.M.; Naash, M.I. Structural characterization of the second intra-discal loop of the photoreceptor tetraspanin RDS. FEBS J. 2013, 280, 127–138. [Google Scholar] [CrossRef]
- Stuck, M.W.; Conley, S.M.; Naash, M.I. PRPH2/RDS and ROM-1: Historical context, current views and future considerations. Prog. Retin. Eye Res. 2016, 52, 47–63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cascella, R.; Strafella, C.; Longo, G.; Manzo, L.; Ragazzo, M.; De Felici, C.; Gambardella, S.; Marsella, M.L.T.; Novelli, G.; Borgiani, P.; et al. Assessing individual risk for AMD with genetic counseling, family history, and genetic testing. Eye 2017, 32, 446–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Strafella, C.; Caputo, V.; Galota, M.R.; Zampatti, S.; Marella, G.; Mauriello, S.; Cascella, R.; Giardina, E. Application of precision medicine in neurodegenerative diseases. Front Neurol. 2018, 9, 701. [Google Scholar] [CrossRef] [PubMed]
Gene | Locus | OMIM | Size of the Target (bp) | Exons | Transcript ID | Coverage (%) |
---|---|---|---|---|---|---|
RHO | 3q22.1 | 180380 | 1147 | 5 | ENST00000296271.3 | 100 |
PRPF31 | 19q13.42 | 606419 | 1760 | 14 | ENST00000321030.8 | 100 |
PRPH2 | 6p21.1 | 179605 | 1101 | 3 | ENST00000230381.6 | 100 |
RP1 | 8q11.2-q12.1 | 603937 | 6531 | 4 | ENST00000220676.1 | 100 |
IMPDH1 | 7q32.1 | 146690 | 2154 | 17 | ENST00000338791.10 | 88.21 |
PRPF8 | 17p13.3 | 607300 | 7848 | 43 | ENST00000304992.10 | 100 |
KLHL7 | 7p15.3 | 611119 | 2060 | 11 | ENST00000339077.9 | 100 |
NR2E3 | 15q23 | 604485 | 1398 | 8 | ENST00000617575.4 | 100 |
CRX | 19q13.33 | 602225 | 960 | 4 | ENST00000221996.11 | 91.77 |
PRPF3 | 1q21.2 | 607301 | 2352 | 16 | ENST00000324862.6 | 100 |
TOPORS | 9p21.1 | 609507 | 3198 | 3 | ENST00000360538.6 | 100 |
USH2A | 1q41 | 608400 | 17043 | 72 | ENST00000307340.7 | 100 |
ABCA4 | 1p22.1 | 601691 | 7822 | 50 | ENST00000370225.3 | 100 |
PDE6A | 5q32 | 180071 | 3023 | 22 | ENST00000255266.9 | 100 |
PDE6B | 4p16.3 | 180072 | 3005 | 22 | ENST00000496514.5 | 98.2 |
RPE65 | 1p31.3 | 180069 | 1882 | 14 | ENST00000262340.5 | 100 |
CNGA1 | 4p12 | 123825 | 2460 | 10 | ENST00000402813.7 | 100 |
BEST1 | 11q12.3 | 607854 | 2214 | 9 | ENST00000449131.6 | 100 |
SEMA4A | 1q22 | 607292 | 2566 | 15 | ENST00000368285.7 | 99.96 |
EYS | 6q12 | 612424 | 10368 | 43 | ENST00000503581.5 | 100 |
CRB1 | 1q31.3 | 604210 | 4616 | 12 | ENST00000367400.7 | 100 |
CERKL | 2q31.3 | 608381 | 1957 | 13 | ENST00000410087.7 | 90.5 |
RPGR | Xp11.4 | 312610 | 4382 | 15 | ENST00000378505.7 | 82.25 |
RP2 | Xp11.3 | 300757 | 1153 | 5 | ENST00000218340.3 | 100 |
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Share and Cite
Strafella, C.; Caputo, V.; Pagliaroli, G.; Iozzo, N.; Campoli, G.; Carboni, S.; Peconi, C.; Galota, R.M.; Zampatti, S.; Minozzi, G.; et al. NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene. Genes 2019, 10, 792. https://doi.org/10.3390/genes10100792
Strafella C, Caputo V, Pagliaroli G, Iozzo N, Campoli G, Carboni S, Peconi C, Galota RM, Zampatti S, Minozzi G, et al. NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene. Genes. 2019; 10(10):792. https://doi.org/10.3390/genes10100792
Chicago/Turabian StyleStrafella, Claudia, Valerio Caputo, Giulia Pagliaroli, Nicola Iozzo, Giulia Campoli, Stefania Carboni, Cristina Peconi, Rosaria Maria Galota, Stefania Zampatti, Giulietta Minozzi, and et al. 2019. "NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene" Genes 10, no. 10: 792. https://doi.org/10.3390/genes10100792