Family based whole Exome sequencing for susceptible genes bearing novel variants associated with juvenile onset open angle glaucoma

Abstract

 

Purpose

 

Primary Juvenile onset Open angle glaucoma ( JOAG) with an age of onset between 10-40years is phenotypically distinct from adult onset open angle glaucoma. Almost 80% of the patients do not have a known genetic mutation, which leaves room for investigating the genetic alterations leading to high IOP and a severe disease manifestation. We aimed to use exome sequencing to detect novel variants in four distinct JOAG patients and their parents, some of whom were affected and others unaffected.

 

Methods

 

Out of the four trios, one had both parents with adult onset POAG, the second had the father affected , the third was a consanguineous marriage with both parents unaffected and the fourth was a non consanguineous marriage with parents unaffected( Fig 1). All our JOAG patients had open angles on gonioscopy but some form of angle dysgenesis was evident in all the 4 probands.<br /> The Illumina NGS platform was used for performing whole exome sequencing, to identify common and differentiating SNPs and structural variations between and across the families to get insight into various genes and pathways modified in the disease. Rare functional variants (RFVs) were considered as those that had 1% or unknown minor allele frequency according to publicly available databases (dbSNP and 1000 genomes project) and that altered the open reading frame of the encoded protein (non synonymous amino acid changes, frameshifts, truncations, non-frameshifting indels, splice site alterations and stop codon losses).

 

Results

 

We detected several rare variants on following genes: ABCD5, AQP7, CDH23 and CDHR1 carrying discriminating structural variations between and across the families. On chromosome 5, there were 46 genes (Specifically at 5q31 loci - 27 genes) that had multiple variations including insertion and deletions. We also found that genes involved in Keratin Filament, calcium dependant cell-cell adhesion and c-myc pathway were perturbrated.

 

Conclusions

 

Multiple genetic variants may be responsible for a single pathway leading to goniodysgenesis that manifests as high IOP in juvenile onset open angle glaucoma pathogenesis.  

 

Four trios selected for exome sequencing