Whole Exome Sequencing in Familial Primary Comitant Exotropia
Zia Chaudhuri, FRCS (Glasg), FICO; Jibin John, PhD; Anirban Mukhopadhyay, MSc; Satinder Aneja, MD; BK Thelma, PhD
Lady Hardinge Medical College and Department of Genetics, University of Delhi South Campus
New Delhi, India
Introduction: Familial forms of primary concomitant strabismus (PCS) support a genetic basis for the condition, which remains an enigma. A few loci have been linked to PCS so far. We performed whole exome sequencing (WES) in an informative family of self-reported north Indian ancestry with exotropia (XT) in an attempt to identify genetic determinants of PCS.
Methods: A three-generation family manifesting presumptive autosomal dominant (AD) XT was recruited. Complete ophthalmic evaluation was done on five affected and three unaffected family members alongwith pedigree documentation. WES of all the samples was performed and analyzed on a standard bioinformatic pipeline.
Results: WES analysis identified three rare heterozygous missense variants in 3 genes, one on chromosome 1 and two on the long and short arms of chromosome 11, segregating with the phenotype and confirmed by Sanger sequencing. Subsequent Sanger sequencing based mutation screening performed in an independent PCS cohort comprising both familial and sporadic cases identified two additional rare variants in one sporadic and one familial case with XT. In silico analysis showed both these variants to be damaging. Computational gene-gene interaction networks were made to study possible role of these variants in ocular motility disorders.
Discussion: WES revealed three rare damaging variants in one gene in two familial and one sporadic case of XT. While the interpretations have to be cautious, these results encourage replication efforts in other ethnic populations and functional validation of the findings.
Conclusion: WES in informative families with PCS may reveal likely causal or contributory genetic determinants of the same.
References: 1. Chaudhuri Z, John A, Aneja S, Thelma BK. Pedigree analysis of familial primary concomitant horizontal strabismus in Northern India. Strabismus 2017 Aug 10: 1-14 (Epub ahead of print)
2. Chaudhuri Z, John A, Aneja S, Thelma BK. Identification of a novel putative variant in the EPHA2 gene on chromosome 1p in a family with exotropia by whole exome sequencing. Oral presentation at the ARVO 2017; Program No 3439; Strabismus: Basic and Clinical Session on May 9, 2017 (ARVO 2017 Annual Program Abstracts)