Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees Following Initial Negative Findings on Panel-Based Next Generation Sequencing

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jan 21

PMID 35055178

Authors

Kirk A J Stephenson

Julia Zhu

Adrian Dockery

Laura Whelan

Tomas Burke

Jacqueline Turner

James J OByrne

G Jane Farrar

David J Keegan

Affiliations

Soon will be listed here.

Abstract

Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70-80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.

Citing Articles

18-Years of single-centre DNA testing in over 7000 index cases with inherited retinal dystrophies and optic neuropathies.

Kiel C, Biasella F, Stohr H, Rating P, Spital G, Kellner U Sci Rep. 2024; 14(1):25529.

PMID: 39462066 PMC: 11513943. DOI: 10.1038/s41598-024-77014-4.

The Role of the Ophthalmic Genetics Multidisciplinary Team in the Management of Inherited Retinal Degenerations-A Case-Based Review.

Conway M, Stephenson K, Zhu J, Dockery A, Burke T, Turner J Life (Basel). 2024; 14(1).

PMID: 38255722 PMC: 10817299. DOI: 10.3390/life14010107.

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review.

Stephenson K, Whelan L, Zhu J, Dockery A, Wynne N, Cairns R Invest Ophthalmol Vis Sci. 2023; 64(10):23.

PMID: 37466950 PMC: 10362925. DOI: 10.1167/iovs.64.10.23.

The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.

Peter V, Kaminska K, Santos C, Quinodoz M, Cancellieri F, Cisarova K PNAS Nexus. 2023; 2(3):pgad043.

PMID: 36909829 PMC: 10003751. DOI: 10.1093/pnasnexus/pgad043.

COVID-19 Vaccines in Inherited Retinal Degenerations (IRD), Fears, Ideas and Real Interactions.

Vingolo E Clin Ophthalmol. 2022; 16:1413-1417.

PMID: 35529953 PMC: 9075903. DOI: 10.2147/OPTH.S358558.

References

Siemiatkowska A, Collin R, den Hollander A, Cremers F . Genomic approaches for the discovery of genes mutated in inherited retinal degeneration. Cold Spring Harb Perspect Med. 2014; 4(8). PMC: 4109577. DOI: 10.1101/cshperspect.a017137. View

Khan M, Cornelis S, Del Pozo-Valero M, Whelan L, Runhart E, Mishra K . Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics. Genet Med. 2020; 22(7):1235-1246. DOI: 10.1038/s41436-020-0787-4. View

Zampaglione E, Kinde B, Place E, Navarro-Gomez D, Maher M, Jamshidi F . Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. Genet Med. 2020; 22(6):1079-1087. PMC: 7272325. DOI: 10.1038/s41436-020-0759-8. View

Farouni R, Djambazian H, Ferri L, Ragoussis J, Najafabadi H . Model-based analysis of sample index hopping reveals its widespread artifacts in multiplexed single-cell RNA-sequencing. Nat Commun. 2020; 11(1):2704. PMC: 7264361. DOI: 10.1038/s41467-020-16522-z. View

Prokofyeva E, Troeger E, Wilke R, Zrenner E . Early visual symptom patterns in inherited retinal dystrophies. Ophthalmologica. 2011; 226(3):151-6. DOI: 10.1159/000330381. View

Hims M, Diager S, Inglehearn C . Retinitis pigmentosa: genes, proteins and prospects. Dev Ophthalmol. 2003; 37:109-25. DOI: 10.1159/000072042. View

Liew G, Michaelides M, Bunce C . A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open. 2014; 4(2):e004015. PMC: 3927710. DOI: 10.1136/bmjopen-2013-004015. View

Beryozkin A, Shevah E, Kimchi A, Mizrahi-Meissonnier L, Khateb S, Ratnapriya R . Whole Exome Sequencing Reveals Mutations in Known Retinal Disease Genes in 33 out of 68 Israeli Families with Inherited Retinopathies. Sci Rep. 2015; 5:13187. PMC: 4549705. DOI: 10.1038/srep13187. View

Heath Jeffery R, Mukhtar S, McAllister I, Morgan W, Mackey D, Chen F . Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia. Ophthalmic Genet. 2021; 42(4):431-439. PMC: 8315212. DOI: 10.1080/13816810.2021.1913610. View

10.

Haer-Wigman L, van Zelst-Stams W, Pfundt R, van den Born L, Klaver C, Verheij J . Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017; 25(5):591-599. PMC: 5437915. DOI: 10.1038/ejhg.2017.9. View

11.

Molina-Ramirez L, Kyle C, Ellingford J, Wright R, Taylor A, Bhaskar S . Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders. J Med Genet. 2021; 59(4):393-398. PMC: 8961756. DOI: 10.1136/jmedgenet-2020-107303. View

12.

Whelan L, Dockery A, Wynne N, Zhu J, Stephenson K, Silvestri G . Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland. Genes (Basel). 2020; 11(1). PMC: 7016747. DOI: 10.3390/genes11010105. View

13.

Cho A, Lima de Carvalho Jr J, Tanaka A, Jauregui R, Levi S, Bassuk A . Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results. Orphanet J Rare Dis. 2020; 15(1):32. PMC: 6993391. DOI: 10.1186/s13023-020-1312-1. View

14.

Smedley D, Smith K, Martin A, Thomas E, McDonagh E, Cipriani V . 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N Engl J Med. 2021; 385(20):1868-1880. PMC: 7613219. DOI: 10.1056/NEJMoa2035790. View

15.

Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino F, Parmeggiani F . Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011; 12(4):238-49. PMC: 3131731. DOI: 10.2174/138920211795860107. View

16.

Van Cauwenbergh C, Van Schil K, Cannoodt R, Bauwens M, Van Laethem T, De Jaegere S . arrEYE: a customized platform for high-resolution copy number analysis of coding and noncoding regions of known and candidate retinal dystrophy genes and retinal noncoding RNAs. Genet Med. 2016; 19(4):457-466. PMC: 5392597. DOI: 10.1038/gim.2016.119. View

17.

Qian X, Wang J, Wang M, Igelman A, Jones K, Li Y . Identification of Deep-Intronic Splice Mutations in a Large Cohort of Patients With Inherited Retinal Diseases. Front Genet. 2021; 12:647400. PMC: 7960924. DOI: 10.3389/fgene.2021.647400. View

18.

Fadaie Z, Whelan L, Ben-Yosef T, Dockery A, Corradi Z, Gilissen C . Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases. NPJ Genom Med. 2021; 6(1):97. PMC: 8602293. DOI: 10.1038/s41525-021-00261-1. View

19.

Koenig R . Bardet-Biedl syndrome and Usher syndrome. Dev Ophthalmol. 2003; 37:126-40. DOI: 10.1159/000072043. View

20.

Dockery A, Whelan L, Humphries P, Farrar G . Next-Generation Sequencing Applications for Inherited Retinal Diseases. Int J Mol Sci. 2021; 22(11). PMC: 8198572. DOI: 10.3390/ijms22115684. View