Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Angela S Li; Gabriel Velez; Benjamin Darbro; Marcus A Toral; Jing Yang; Stephen H Tsang; Polly J Ferguson; James C Folk; Alexander G Bassuk; Vinit B Mahajan

doi:10.1016/j.ajo.2020.07.021

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Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Journal article

Peer reviewed

Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Angela S Li, Gabriel Velez, Benjamin Darbro, Marcus A Toral, Jing Yang, Stephen H Tsang, Polly J Ferguson, James C Folk, Alexander G Bassuk and Vinit B Mahajan

American journal of ophthalmology, Vol.221, pp.246-259

01/2021

DOI: 10.1016/j.ajo.2020.07.021

PMCID: PMC7736069

PMID: 32707200

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https://www.ncbi.nlm.nih.gov/pmc/articles/7736069View

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Abstract

To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach. Genetic association cohort study. Setting: Single-center study at an academic referral center. 164 patients with clinically diagnosed uveitis of the posterior segment. Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling, and in silico calculations were then used to rank and predict the functional consequences of key variants. A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis-such as NOD2 (Blau syndrome) and CAPN5 NIV (neovascular inflammatory vitreoretinopathy)-as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type. This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole-exome sequencing can help diagnose nonsyndromic uveitis in patients harboring known variants for syndromic inflammatory diseases.

Inflammasomes - metabolism

Genetic Association Studies

Humans

Middle Aged

NLR Proteins - genetics

Child, Preschool

Uveitis, Posterior - metabolism

Male

Mutation, Missense

Calpain - genetics

Uveitis, Posterior - genetics

Whole Exome Sequencing

Adolescent

Proteomics

Aged, 80 and over

Adult

Female

Aged

TYK2 Kinase - genetics

Child

Details

Title: Subtitle: Whole-Exome Sequencing of Patients With Posterior Segment Uveitis
Creators: Angela S Li - Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA
Gabriel Velez - Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA
Benjamin Darbro - Department of Pediatrics, Medical Genetics and Genomics, University of Iowa, Iowa City, Iowa, USA
Marcus A Toral - Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA
Jing Yang - Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA
Stephen H Tsang - Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Pathology & Cell Biology, College of Physicians & Surgeons (S.H.T.), Columbia University, New York, New York, USA
Polly J Ferguson - Department of Pediatrics, Division of Pediatric Rheumatology, University of Iowa, Iowa City, Iowa, USA
James C Folk - Department of Ophthalmology, University of Iowa, Iowa City, Iowa, USA
Alexander G Bassuk - Department of Neurology and Pediatrics, University of Iowa, Iowa City, Iowa, USA
Vinit B Mahajan - Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA; Veterans Affairs, Palo Alto HCS, Palo Alto, California, USA. Electronic address: vinit.mahajan@stanford.edu
Resource Type: Journal article
Publication Details: American journal of ophthalmology, Vol.221, pp.246-259
DOI: 10.1016/j.ajo.2020.07.021
PMID: 32707200
PMCID: PMC7736069
NLM abbreviation: Am J Ophthalmol
ISSN: 0002-9394
eISSN: 1879-1891
Publisher: United States
Grant note: P30 EY026877 / NEI NIH HHS R01 EY025225 / NEI NIH HHS R01 EY018213 / NEI NIH HHS P30 CA013696 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 EY024698 / NEI NIH HHS R01 AR059703 / NIAMS NIH HHS R01 EY026682 / NEI NIH HHS R01 EY024665 / NEI NIH HHS F30 EY027986 / NEI NIH HHS R21 AG050437 / NIA NIH HHS P30 EY019007 / NEI NIH HHS
Language: English
Date published: 01/2021
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics); Ophthalmology and Visual Sciences
Record Identifier: 9984070874902771

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