A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification
<p>Pedigree depicting 13q12.11 deletion in affected family members and their corresponding phenotypes.</p> "> Figure 2
<p>Clinical features of syndromic corneal opacification family. II-1: Slit lamp (<b>A</b>) and external (<b>B</b>) photos at presentation (age 5 years) and external photos at follow-up after superficial keratectomy (age 13 years) (<b>C</b>) II-2: Slit lamp (<b>D</b>) and external (<b>E</b>) photos at presentation (age 8 years) and external photos at follow-up after superficial keratectomy (age 9 years) (<b>F</b>). The current age of the proband (II-1) is 15, and the proband’s brother (II-2) is 12.</p> "> Figure 3
<p>Chromosome 13q12 microdeletion interval showing genes and overlapping microdeletions. UCSC genome browser region depicting region and involved genes of family’s microdeletion as well as overlapping microdeletions identified by literature review and the DECIPHER database. Browser coordinates use the hg19 genome build. Phenotypes present for each microdeletion are highlighted [<a href="#B13-genes-14-01034" class="html-bibr">13</a>,<a href="#B14-genes-14-01034" class="html-bibr">14</a>,<a href="#B15-genes-14-01034" class="html-bibr">15</a>].</p> "> Figure 4
<p>Region-focused DEGs analysis. A Heatmap showing the normalized Z-scores and log<sub>2</sub> fold changes (log<sub>2</sub>fc) for the genes in/around the microdeletion, as well as their average corneal expression in normalized counts (AvgExp) across the samples.</p> "> Figure 5
<p>RNAseq analysis from corneal epithelium. (<b>A</b>) A volcano plot showing the DESeq2 comparison of global gene expression between a corneal epithelial sample from our case and controls (healthy, mildly myopic patients). Green is log<sub>2</sub> fold change (FC) >|2| and <span class="html-italic">p</span>-value > 10<sup>−6</sup>; blue is log<sub>2</sub> fold change <|2| and <span class="html-italic">p</span>-value < 10<sup>−6</sup>; red is log<sub>2</sub> fold change >|2| and <span class="html-italic">p</span>-value < 10<sup>−6</sup>. (<b>B</b>) A scatter plot showing the fold enrichment of the top ten most significantly upregulated Gene Ontology (GO) processes from our case sample as determined by the lowest false discovery rate (FDR). TM, tube morphogenesis; BVM, blood vessel morphogenesis; CMP, collagen metabolic processes; TD, tube development; VD, vasculature development; BVD, blood vessel development; EESO, external encapsulating structure organization; EMO, extracellular matrix organization; CFO, collagen fibril organization.</p> "> Figure 6
<p>Model for dysregulated gene expression leading to corneal opacification phenotype. EGF and TGFβ signaling work synergistically to promote ECM protein formation/deposition in the cornea, a process negatively regulated by four of the genes lost in the microdeletion: <span class="html-italic">XPO4</span>, <span class="html-italic">LATS2</span>, <span class="html-italic">ZDHHC20</span>, and <span class="html-italic">IFT88</span>. <span class="html-italic">LATS2</span> is thought to inhibit TGFβ signaling through its role in the YAZ/TAP pathway, whereas <span class="html-italic">XPO4</span> inhibits the function/localization of key TGFβ effector SMAD3. Additionally, <span class="html-italic">ZDHHC20</span> inhibits EGF signaling via palmitoylation of EGF receptors (EGFR). <span class="html-italic">IFT88</span> works downstream of both pathways in regulating the ECM through its roles in collagen production/fiber organization, Hedgehog signaling, ciliary calcium response, and protease endocytosis. The loss of one or more of these genes could thus result in the inappropriate accumulation of ECM proteins in the anterior cornea, triggering a fibrotic response and resulting in a progressive haze.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Clinical Testing
2.2. RNAseq Analysis
3. Results
3.1. Clinical Report
3.1.1. Proband (II-1)
3.1.2. Proband’s Brother (II-2)
3.1.3. Proband’s Parents
3.2. Genetic Analysis
3.3. RNAseq Analysis
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variant (hg19 Coordinates) | Overlapping Phenotype | Includes XPO4/CRYL1 | Reference |
---|---|---|---|
del 13: 20,079,051–25,514,640 | Laryngomalacia; motor, language, and speech delays | XPO4, CRYL1 | DECIPHER ID 282712 |
del 13: 20,407,295–22,453,812 | Developmental delay | XPO4, CRYL1 | DECIPHER ID 317099 |
del 13: 19,938,561–22,840,254 | Developmental delay, speech delay | XPO4, CRYL1 | Lagou et al. [14] |
del 13: 20,174,448–23,128,904 | Developmental delay affecting speech and language, recurrent otitis media, conductive hearing loss | XPO4, CRYL1 | Tanteles et al. [15] |
del 13: 20,521,989–22,617,211 | Developmental delay | XPO4, CRYL1 | Der Kaloustian et al. [13] |
del 13: 20,808,367–21,001,431 | Intellectual disability, sensorineural hearing impairment | CRYL1 * | DECIPHER ID 273408 |
del 13: 20,808,544–21,078,913 | Bilateral conductive hearing impairment | CRYL1 * | DECIPHER ID 379530 |
del 13: 20,797,139–21,059,969 | Intellectual disability, sensorineural hearing impairment | CRYL1 | DECIPHER ID 285395 |
del 13: 20,281,273–21,945,915 | Laryngomalacia, stridor | XPO4, CRYL1 | DECIPHER ID 384469 |
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Serpen, J.Y.; Presley, W.; Beil, A.; Armenti, S.T.; Johnson, K.; Mian, S.I.; Innis, J.W.; Prasov, L. A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification. Genes 2023, 14, 1034. https://doi.org/10.3390/genes14051034
Serpen JY, Presley W, Beil A, Armenti ST, Johnson K, Mian SI, Innis JW, Prasov L. A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification. Genes. 2023; 14(5):1034. https://doi.org/10.3390/genes14051034
Chicago/Turabian StyleSerpen, Jasmine Y., William Presley, Adelyn Beil, Stephen T. Armenti, Kayla Johnson, Shahzad I. Mian, Jeffrey W. Innis, and Lev Prasov. 2023. "A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification" Genes 14, no. 5: 1034. https://doi.org/10.3390/genes14051034