Next-Generation Sequencing in Congenital Eye Malformations: Identification of Genetic Causes and Comparison of Different Panel-Based Diagnostic Strategies

TL;DR

This study uses next-generation sequencing to identify genetic causes of congenital eye malformations and compares different testing strategies to improve diagnosis.

Contribution

The study introduces a stepwise genetic testing approach using broad multigene panels and exome sequencing for higher diagnostic yield in eye malformations.

Findings

Causative variants were identified in 43% of patients using a stepwise NGS approach.

Diagnostic rates were highest in patients with complex ocular phenotypes and positive family history.

Eight novel (likely) pathogenic variants in six genes were discovered.

Abstract

Congenital eye malformations like microphthalmia–anophthalmia–coloboma (MAC), anterior segment dysgenesis (ASD), primary congenital glaucoma (PCG) and congenital cataracts (CC) are significant causes of childhood visual impairment. Phenotypic heterogeneity often complicates diagnosis. The goal of this study was to optimize the diagnostic strategy for next-generation sequencing (NGS)-based procedures, thereby aiming to identify genetic causes of congenital eye malformations. Forty patients with congenital eye malformations were included. A primary diagnostic testing (PD) of a limited number of genes was followed by multigene panel (MGP) testing, including 186 eye-related genes, and exome sequencing. Causative variants were identified in 17 patients (43%) and clinically relevant variants of uncertain significance (VUS) in 6 patients (15%). PD had a diagnostic yield (DY) of 15%, MGP of 29% and exome sequencing of 4%, leading to a cumulative DY of 43%. Diagnostic rates were highest in CC (75%), bilateral cases (46%), complex ocular phenotypes (78%), patients with extraocular manifestations (55%) and positive family history (70%). Rare and possible new genotype–phenotype correlations and candidate genes (FAT1, POGZ) could be identified. In total, eight (likely) pathogenic variants in six genes (CYP1B1, ADAMTS18, MAB21L2, NHS, MFRP, CRYBB1) were not yet reported. A stepwise genetic testing approach starting with a broad multigene panel followed by exome sequencing provides higher diagnostic yield than limited phenotype-specific testing. Comprehensive genetic diagnosis is essential for prognosis, treatment and genetic counseling, underscoring the need for routine genetic testing and interdisciplinary collaboration in managing congenital eye malformations.

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