Abstract
Purpose :
We performed whole genome sequencing (WGS) to identify the possible genetic cause of juvenile open angle glaucoma (JOAG) in a patient with neurodevelopmental disorder (NDD). The objective of this report is to highlight the importance of WGS analysis in expanding the genomic profile for early onset glaucoma (EOG).
Methods :
A 2 generation family with 4 individuals were recruited to participate in the study. Each subject underwent a comprehensive ophthalmologic evaluation and blood sample collection for WGS. The Seqr platform was utilized for variant prioritization and includes in-silico prediction tools, population reference databases, gene and tissue expression.
Results :
A 14 year old male patient with NDD and JOAG presented with bilateral eye redness and poor visual acuity. Intraocular pressure (IOP) was elevated at 38mmHg bilaterally with cup to disc ratio (CDR) of 0.9 OU. An ARID1B heterozygous, premature nonsense variant, c.1906C>T (p.Gln636Ter), was identified in the affected child and not in parents or siblings suggesting that the mutation is de novo. Multiple in-silico prediction tools determined this variant as pathogenic (CADD: 38; Eigen 20.9). The variant is not found in population databases such as gnomAD, LOVD and ClinVar. In the descartes human cell atlas of fetal gene expression, ARID1B is expressed in 32% of the cells in the developing eye.
Conclusions :
A novel de novo ARID1B nonsense mutation is proposed as the genetic cause of the patient’s glaucoma. This gene encodes a subunit of the SWI/SNF DNA chromatin remodeling complex that regulates gene expression through genome targeting and transcription factor interaction involving the intrinsically disordered region of ARID1B. ARID1B is a known cause of Coffin Siris syndrome, however this patient did not exhibit the clinical features defining this syndrome other than mental retardation. Previous reports have identified 2 other patients with EOG and ARID1B mutations. Interestingly, glaucoma has not been reported in any patient with Coffin Siris syndrome caused by any of the other 9 genes that can cause this syndrome suggesting that glaucoma may be a unique feature of patients with ARID1B mutations. Of interest is a potential interaction between ARID1B and EEFMP1, a gene known to cause early-onset glaucoma. Further work is needed to define the mechanism of glaucoma development in patients with ARID1B mutations.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.