Molecular diagnostic challenges for non‐retinal developmental eye disorders in the United Kingdom

Abstract

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.

Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia

“…Pathogenic variants in over 100 genes have been reported to cause microphthalmia, anophthalmia, and coloboma (MAC) or anterior segment dysgenesis (ASD) spectrum phenotypes, with the highest proportion of cases explained by disruption of transcription factors/regulators 1‐3 . While a greater number of genes are reported to result in MAC phenotypes, diagnostic rates for ASD conditions are typically higher, ranging from 25–60% for ASD versus 15–30% for MAC 3‐6 . Rates of genetic diagnosis are lower in cases with unilateral ocular anomalies, typically 4–10% in unilateral MAC, for example, 3,7 and these conditions are often regarded as less‐likely to be due to a genetic etiology.…”

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia

“…SLC38A8-oculopathy may well be under diagnosed because of its subtle presentation, easily confused with albinism. Current molecular diagnostic rates for albinism and nystagmus using WGS are approximately 28% [13]. Until recently, SLC38A8 was not included in the albinism and nystagmus targeted gene panels.…”

“…There are 37 reported mutations to date, and along with our novel variants these span all 10 exons (Figure 2A). The genotype of families 1, 3, 4 and 5 were reported in our previous study reporting the genetic outcomes of a large cohort of non-retinal developmental eye disease patients recruited into the 100,000 Genomes Project, but no detailed phenotype data was provided [13]. Variants were shown to be in trans in five of seven families where parents, all unaffected, were available for segregation analysis.…”

Introduction to the special issue on Ophthalmic Genetics: Vision in 2020

“…In contrast, ocular malformations represent a group of disorders seemingly intolerant to defining monogenic etiologies. Three papers herein describe limitations in diagnostic testing for developmental eye malformations (Jackson et al, 2020), experimental animal models for validating candidate disease genes (Yoon et al, 2020), and ocular manifestations of CHARGE syndrome in patients without coloboma (Dosunmu et al, 2020). Finally, this section concludes with a series of papers highlighting the wide spectrum of disorders arising from the same genetic locus.…”

“…In contrast, ocular malformations represent a group of disorders seemingly intolerant to defining monogenic etiologies. Three papers herein describe limitations in diagnostic testing for developmental eye malformations(Jackson et al, 2020), experimental animal models for validating candidate disease genes(Yoon et al, 2020), and ocular manifestations of CHARGE syndrome in patients without coloboma(Dosunmu et al, 2020).Finally, this section concludes with a series of papers highlighting the wide spectrum of disorders arising from the same genetic locus. These include novel clinical and molecular descriptions of adult forms of peroxisomal disorders (Heimler syndrome; Daich Varela et al, 2020), inborn errors of metabolism (Nonsyndromic retinal degeneration; Schiff et al, 2020), and the wide spectrum of ocular phenotypes arising from postzygotic genetic mosaicism (Coffin-Siris syndrome; Miraldi Utz et al, 2020).…”