A Novel 13q12 Microdeletion Associated with Familial Syndromic Corneal Opacification

Area of Science:

• Genetics and Ophthalmology
• Molecular Biology
• Medical Genetics

Background:

• Progressive corneal opacification has diverse causes, including genetic and systemic conditions.
• Syndromic presentations involving ocular, auditory, and respiratory systems are complex and require detailed genetic investigation.

Purpose of the Study:

• To characterize a novel syndrome presenting with progressive corneal opacification, sensorineural hearing loss, and tracheomalacia/laryngomalacia.
• To identify the genetic basis of this syndromic condition through molecular and chromosomal analysis.

Main Methods:

• Clinical evaluation of affected family members (brother, sister, father) with syndromic features.
• Chromosomal microarray and clinical exome sequencing to identify genetic variants.
• RNA sequencing (RNAseq) of corneal epithelial samples to analyze gene expression within the deleted region.

Main Results:

• A 1.2 Mb deletion at chromosome 13q12.11 was identified in all affected family members.
• RNAseq revealed downregulation of several genes (e.g., XPO4, IFT88) within the microdeletion.
• Pathway analysis indicated upregulation of collagen metabolism and extracellular matrix (ECM) formation, suggesting ECM dysregulation.

Conclusions:

• The study defines a novel microdeletion-associated syndrome characterized by progressive corneal opacification, sensorineural hearing loss, and airway abnormalities.
• The findings suggest that dysregulation of ECM formation, potentially due to the combined effect of deleted genes, underlies the observed pathogenesis.
• Variants in XPO4 and genes in the DFNB1 locus are associated with some features, but the novel microdeletion appears to be the primary driver of the complete syndromic phenotype.