Comprehensive Genetic Testing Identifies Rare Pathogenic Variants for Anterior Segment Dysgenesis

Abstract

Purpose : Anterior segment dysgenesis (ASD) comprises a wide spectrum of ocular anomalies of the cornea, iris, and lens. ASD may involve only the eye or may be part of a systemic syndrome. Causative variants in eight genes have been identified in isolated ASD. Over 40 syndromes include ASD as a finding. In this study, we aim to reveal DNA variants in known and novel genes underlying various types of ASD in order to better define the spectrum of causative variants.

Methods : Probands from 34 unrelated families and their available first degree relatives were included. In 10 probands with isolated ASD, we screened mutations in known ASD genes via next-generation sequencing gene panels. In the remaining 24 probands with isolated or syndromic ASD, we performed whole exome sequencing. We analyzed the next-generation sequencing data for single nucleotide variants, small indels and copy number variants. Sanger sequencing was used to confirm variants and evaluate their segregation in available family members.

Results : Overall, we identified 16 rare and likely causative variants (6 novel) in 13 of the families (38%). Each variant was observed only in one family. Single nucleotide variants and small indels in isolated ASD genes include those in FOXC1 (4 families heterozygous; 1 novel), CYP1B1 (2 families; 1 family homozygous and 1 family compound heterozygous), PXDN (1 family compound heterozygous; 2 novel), FOXE3 (1 family homozygous; novel), and PAX6 (1 family heterozygous). In addition, a child with bilateral aniridia and glaucoma is heterozygous for a large deletion including PAX6. Syndromic ASD genes with causative variants are BMP4 (syndromic microphthalmia 6; 1 family heterozygous; novel), B3GLCT (Peters Plus syndrome; 1 family compound heterozygous; 1 novel) and GJA1 (oculodentodigital dysplasia; 1 family heterozygous). One patient with Peters anomaly is compound heterozygous for two PXDN variants; causative variants in PXDN have not previously been reported in this condition. Further analysis for variants in novel genes is ongoing.

Conclusions : Comprehensive analysis of DNA variants via next-generation sequencing allows us to search for causative variants in known genes with an advantage of whole exome sequencing to include potential novel genes. Underlying genetic causes of ASD are very heterogeneous; only less than half can be detected in known genes.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.