Abstract
Purpose :
Childhood glaucoma (CG) is a rare heritable disorder, and is a major category for childhood blindness. Uncontrolled high intraocular pressure can lead to globe enlargement, corneal expansion with clouding, and retinal ganglion cell/optic nerve damage causing impaired vision and possible blindness. To date, genetic studies explain just over half of the disease etiology. We sought to identify novel molecular causes of CG in a cohort of families with no known gene variants.
Methods :
Once consented with approved human subjects protocols, medical histories and samples for DNA extraction were obtained from patient subjects. Exome sequencing was performed on the affected probands using Sure Select Human All Exon capture kit (version 5/6) or Twist exome (34 MB capture target) on an Illumina HiSeq 2000/2500 or NovaSeq 6000 platform, respectively. Sequence analysis was performed using Golden Helix SVS software. Variants that were non-coding, synonymous, or with an allele frequency greater than 0.002 (gnomAD population datasets) were removed. Variants in probands were confirmed and genotypes of available family members were identified via Sanger sequencing.
Results :
Three families of 78 were identified with heterozygous TIE1 variants (p.Glu172Lys, p.Arg279Gln, p.Ile1046Thr). Global and ethnically matched population allele counts were low for all variants. Protein sequence alignments from 100 vertebrates showed conservation of the reference residues. All variants were predicted to be detrimentally affected functionally by in silico programs MutationTaster, FATHMM, and CADD.
Conclusions :
Herein, we present the first reported human variants in TIE1 associated with childhood glaucoma. TIE1 is a transmembrane protein required for the development, integrity, and survival of vascular endothelial cells, and is strongly expressed in Schlemm’s canal (SC). SC is an endothelial-lined structure with characteristics of both lymphatic and blood vessels, and its development is essential for aqueous humor drainage. Mice lackingTie1 develop an aberrant SC, resulting in impaired aqueous humor outflow with consequent increase in intraocular pressure. We propose that heterozygous variants in TIE1 are a potential cause of autosomal dominant CG, similar to its associated pathway members TEK (TIE2) and ANGPT1.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.