Abstract
Purpose :
Congenital Microcoria (MCOR) is a rare ocular disease characterized by abnormally small pupils due to absence of the dilator pupillae muscle. MCOR has been associated with early onset glaucoma in some cases. The disease is inherited as a dominant trait and large-scale chromosomal rearrangements (mainly deletions) involving 13q32.1 have been identified. In this study, we identify a novel 13q32.1 deletion in a Filipino MCOR family involving TGDS and GPR180 genes as well as a putative SOX21 regulatory region providing additional insight into the genetic etiology of this condition.
Methods :
4 members from a 4 generation Filipino family with 32 individuals were recruited for the study. Subjects underwent comprehensive ophthalmologic examination and DNA extraction. Whole genome sequencing was performed, SNP and indel variant calling workflows were followed using GATK Best Practices, and structural variants were mapped using the GATK-SV pipeline. SNPs and indels were analyzed using seqr and SVs with Integrated Genomics Viewer. Single cell RNA sequence data was accessed from the Broad single cell portal.
Results :
Abnormally small pupils (<2mm) were observed in 3 of the 4 family members enrolled in the study. Intraocular pressures were within normal range for all subjects except for the 16 year old proband (IOP in the 50s) who was also diagnosed with early onset glaucoma requiring surgical interventions. Screening for mutations causing early onset glaucoma and other potential variants was inconclusive. Analyses of copy number variants (CNVs) revealed a 37-kilobase deletion on chromosome 13q32.1 in all 3 affected members and not in the unaffected member. The deletion extended from 13:94,590,353 to 94,637,698 encompassing GPR180 and TGDS genes and a regulatory region containing enhancers for SOX21. Single cell RNA data suggests expression in iris and ciliary body for both GPR180 and TGDS but with GPR180 having higher expression at 78% and 54% respectively.
Conclusions :
Large scale 13q32.1 deletions involving GPR180 and TGDS segregate with disease in this Filipino family and together with other deletions previously described support a locus for MCOR in this chromosome region. In addition, a region regulating expression of SOX21, another gene involved in eye development, is also included in the deletion critical region. Further work is needed to define the MCOR causal gene or genes located in 13q32.1.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.