Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0–25 with Bilateral Cataracts

Abstract

Childhood cataract affects 2.5–3.5 per 10,000 children in the UK, with a genetic mutation identified in 50–90% of bilateral cases. However, cataracts can also manifest in adolescence and early adulthood in isolation, as part of a complex ocular phenotype or with systemic features making accurate diagnosis more challenging. We investigate our real-world experience through a retrospective review of consecutive bilateral cataract patients (0–25 years) presenting to the ocular genetics service at Moorfields Eye Hospital between 2017 and 2020. Fifty-four patients from 44 unrelated families were identified, with a median age of 13.5 years (range 1 to 68 years) and a median age at diagnosis of 43.9 months IQR (1.7–140.3 months); 40.7% were female and 46.3% were Caucasian. Overall, 37 patients from 27 families (61.4%) were genetically solved (50%) or likely solved (additional 11.4%), with 26 disease-causing variants (8 were novel) in 21 genes; the most common were crystallin genes, in 8 (29.6%) families, with half occurring in the CRYBB2 gene. There was no significant difference in the molecular diagnostic rates between sporadic and familial inheritance (P = 0.287). Associated clinical diagnoses were retinal dystrophies in five (18.5%) and aniridia in three (11.1%) families. Bilateral cataracts were the presenting feature in 27.3% (6/22) of either complex or syndromic cases, and isolated cataract patients were 11.5 years younger (rank-sum Z = 3.668, P = 0.0002). Prompt genetic investigation with comprehensive panel testing can aid with diagnosis and optimise management of cataract patients.

The utility of genomic testing in the ophthalmology clinic: A review

“…These examples may reflect ethnic biases in gene discovery efforts and control cohorts to date. Some studies have reported different diagnostic rates in sporadic compared to familial cases, 52 whereas others found no difference 30 . It is likely that all these factors as well as differences in disease definitions and inclusion criteria combined with stochastic effects inherent in small studies contribute to the differences.…”

“…In contrast, and more recently, several studies show that for IRDs, which are highly heterogeneous, a well‐curated panel provides greater sensitivity and diagnostic yield than WES, 27,28 and multiple studies demonstrate that panels are able to detect pathogenic variants for some patients in genes not primarily associated with the phenotype 15,27,28 . However, the diagnostic rate varies greatly with phenotypes and is in the range 25%–64% for most studies of varied phenotypes 13,20,24–28,30 . This may be improved with more homogeneous phenotype classification and more considered target panel selection, 21,22,31 but there will remain as substantial number of patients likely requiring additional investigations by WES or WGS to expand the genes tested.…”

“…The diagnostic rate varies considerably with disease, type of test, population and inclusion criteria for studies assessing diagnostic rates. For example, multiple studies for congenital cataract find diagnostic rates of over 70%, 21,22 while others report much lower success rates in the range of 20%–60% 23,30,43–50 . Reasons for these major differences are not immediately clear.…”

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

“…Cataracts have a wide differential diagnosis, including maternally derived infections, iatrogenic, and trauma. However, a molecular cause can be identified for the majority of patients in 1 of 115 associated genes [14,[16][17][18]. Inherited cataracts most commonly occur on their own (70%), but patients may also present with associated ocular (15%) and systemic features (15%).…”

“…Inherited cataracts most commonly occur on their own (70%), but patients may also present with associated ocular (15%) and systemic features (15%). Common additional ocular features include anterior segment dysgenesis, retinal dystrophies, aniridia, and microphthalmia (defined as a small underdeveloped eye, with an axial length of more than two standard deviations below the age adjusted mean) [18,19]. Microphthalmia with cataracts have been associated with mutations in CRYAA, CRYBA4, CRYBB1, CRYBB2, CRYGC, CRYGD, GJA3, FOXE3, PITX3, IPO13, SIPA1L3, VSX2, GJA8, and NHS [16,[20][21][22][23][24][25][26][27].…”