Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Abstract

Purpose: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry

“…11 The highest diagnostic yield was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). This is not surprising considering that the majority of this cohort comprises individuals with ARS which has a reported diagnostic yield of 40-63%, 34,44,45 mainly accounted for by variants in FOXC1 and PITX2. The diagnostic yield improved once probands were reclassified into this category, most of whom had an initial clinical diagnosis of PCG.…”

“…Differences in IOP between subgroups also reached statistical significance (p=0.002). Those with JOAG had a lower median maximum recorded IOP (29 [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] mmHg) compared to those with an associated acquired condition (36 [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] mmHg,…”

“…Childhood and early-onset glaucoma classification and genetics p=0.03) and non-acquired ocular anomalies (39 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] mmHg, p=0.02). The median maximum IOP recorded was 15 [14-17] mmHg among individuals with NTG compared to [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] mmHg among those with HTG (Supplementary Table 1). The median age of diagnosis of disease also reached statistical significance between groups (p=0.03).…”

“…The median age at glaucoma diagnosis was lowest in individuals with CPAMD8 (0 [0-17] years), TEK (0.17 [0-0.25] years) and CYP1B1 variants (0.14 [0-8] years), which is consistent with those who were clinically diagnosed with PCG. The median age at glaucoma diagnosis was highest in individuals with variants in OPTN (33 [30][31][32][33][34][35] years), TBK1 (30 [25][26][27][28][29][30][31][32][33][34][35][36][37][38] years) and MYOC (29 years). These variants were found exclusively in individuals with JOAG with the exception of one individual with a MYOC variant and PCG.…”

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.…”