Abstract
Purpose :
The molecular diagnosis of inherited and developmental eye diseases is complex and requires sophisticated sequencing and bioinformatics approaches. Whole exome sequencing (WES) has proved to be a powerful tool in determining the genetic cause of inherited eye disorders with allelic and locus heterogeneity. The present study takes advantage of molecular tools such as WES to identify the genetic etiology in ten pediatric patients with complex ocular anomalies along with other systemic alterations.
Methods :
We included ten unrelated Mexican pediatric patients that had ocular anomalies and several systemic manifestations of unknown etiology. To all of them we performed a WES study by using genomic DNA extracted from peripheral blood samples. Pathogenicity of candidate variant was evaluated according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. To examine the probable structural consequences of missense variants that were classified as a likely pathogenic (LPV) and variant of uncertain significance (VUS) we carried out an in silico molecular modeling of the proteins.
Results :
From the 10 patients included in this study 8 were males and 2 females. The median read depth for the WES study was 255X (range 185X - 413X) with a 98.9% of coverage. This molecular approach allowed us to identify clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes, in five (50%) out of the ten studied patients. Those mutations located in GZF1, NFIX and TRRAP were classified as pathogenic variants, meanwhile that in FGFR2 as LPV and in PAX2 as a VUS. The protein modeling of the two missense FGFR2: p.(Arg210Gln) and PAX2: p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins.
Conclusions :
The implementation of WES in ten patients with eye abnormalities occurring with other systemic alterations allowed us to identify the genetic cause in 5/10 (50%) of them, associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD and papillorenal syndromes. All these syndromes that we characterized molecularly are very rare. Finally, WES study was helpful in the diagnosis of these patients with phenotypes that may overlap with other genetic entities.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.