June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
A novel 13q12 microdeletion associated with familial syndromic corneal dystrophy
Author Affiliations & Notes
  • William Presley
    Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
  • Jasmine Y Serpen
    School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Adelyn Beil
    Pediatrics, University of Michigan, Ann Arbor, Michigan, United States
  • Stephen T Armenti
    Ophthalmology and Visual Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Kayla Johnson
    School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Shahzad Mian
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Jeffrey W Innis
    Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
    Pediatrics, University of Michigan, Ann Arbor, Michigan, United States
  • Lev Prasov
    Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   William Presley None; Jasmine Serpen None; Adelyn Beil None; Stephen Armenti None; Kayla Johnson None; Shahzad Mian None; Jeffrey Innis None; Lev Prasov None
  • Footnotes
    Support  T32GM007544
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4762. doi:
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    • Get Citation

      William Presley, Jasmine Y Serpen, Adelyn Beil, Stephen T Armenti, Kayla Johnson, Shahzad Mian, Jeffrey W Innis, Lev Prasov; A novel 13q12 microdeletion associated with familial syndromic corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4762.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Corneal dystrophies comprise a group of genetic disorders that feature progressive opacification of the cornea. Here, we report a family exhibiting a novel syndromic corneal dystrophy segregating with a 1.2 Mb deletion within chromosome 13q12.11. We use transcriptomic analysis and clinical data to further characterize the underlying genes and pathways contributing to pathogenesis.

Methods : RNA was extracted from a corneal epithelium sample donated by an affected sibling and underwent Illumina RNAseq. Differentially expressed genes (DEGs) analysis was performed with published corneal epithelial control samples for comparison. Pathway analysis was completed using PANTER Gene-Ontology. ClinVar and GeneMatcher patients with overlapping variants were evaluated for phenotypic concordance.

Results : We report two siblings with progressive bilateral epithelial and anterior stromal haze and sensorineural hearing loss, one of whom also had tracheomalacia. Their father had a milder phenotype with hearing loss, mild corneal opacity, and tracheomalacia. All three family members carried a 1.2 Mb deletion within chromosome 13q12.11. DEGs analysis from corneal epithelial RNA showed downregulation of the following genes within the interval, yet no effect on expression of nearby genes: XPO4 (L2FC=-2.5, p=2.9E-11), IFT88 (L2FC=-2, p=3.7E-4), ZDHHC10 (L2FC=-1.7, p=3.6E-4), LATS2 (L2FC=-1.6, p=2.3E-3), SAP18 (L2FC=-1, p=2.7E-3), and EEF1AKMT1 (L2FC=-1.3, p=7.5E-3). Pathway analysis demonstrated upregulation of SMAD signaling, collagen metabolism, and extracellular matrix (ECM) formation/maintenance with no significantly downregulated pathways. Analysis of overlapping variants revealed that heterozygous, deleterious variants in XPO4 have been identified in patients with laryngomalacia and sensorineural hearing loss, but without reported corneal phenotypes.

Conclusions : We have defined a microdeletion-associated novel form of syndromic corneal dystrophy featuring bilateral corneal haze, sensorineural hearing loss, and tracheomalacia. While the latter symptoms are likely attributable to the loss of XPO4, there is no single gene within the deletion previously linked to the corneal phenotype. Still, ZDHHC20, IFT88, XPO4, and LATS2 all regulate the production/organization of ECM proteins, and thus the loss of one or more may lead to the aberrant production/deposition of ECM in the cornea.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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