The aim of this study was to evaluate the diagnostic yield from prior genetic testing in a 20-year cohort of pediatric patients with congenital cataracts. A retrospective review of patients with congenital cataracts who underwent genetic testing was completed from 2003–2022. The diagnostic yield of the test was determined by variant classification and inheritance pattern. Variants from initial testing underwent reclassification in accordance with ACMG-AMP (American College of Medical Genetics and Genomics—American Association of Molecular Pathology) 2015 or 2020 ACMG CNV guidelines. A total of 95 variants were identified in 52 patients with congenital cataracts (42 bilateral, 10 unilateral); 42 % were White, 37% were Hispanic, 8% were Black, and 6% were Asian. The majority of patients (92%) did not have a family history of congenital cataracts but did have systemic illnesses (77%). Whole exome sequencing and targeted congenital cataract panels showed diagnostic yields of 46.2% and 37.5%, respectively. Microarray had the lowest yield at 11%. Compared to the initial classification, 16% (15 of 92 variants) had discrepant reclassifications. More testing is needed, and an increased focus is warranted in the field of ocular genetics on congenital cataracts, particularly in those with systemic illnesses and no family history, to advance our knowledge of this potentially blinding condition.

To characterize and compare our cohorts of pediatric patients with type I and type II Sticker syndrome, with a focus on ophthalmological features. Retrospective cohort study. Twenty-six patients (22 families) with clinical and genetic diagnoses of types I or II Stickler syndrome. Review of clinical notes and molecular diagnoses. Ophthalmic and systemic features and responses to laser treatment. Our cohorts had an equal number of patients with COL2A1-related/Type I and COL11A1-related/Type II Stickler syndrome (n=13; 50%) and include 12 previously unpublished variants. Patients in Type I and II cohorts had similar average ages at presentation and length of follow-up. There were more self-identifying Hispanic patients among the Type II cohort compared to Type I (69% versus 39%, p = 0.145). Individuals with Type II on average had significantly higher myopia compared to those with Type I (p=0.008). Retinal detachment in at least one eye was diagnosed in 39% of the Type I cohort (7 eyes, 5 patients) and 46% of the Type II (7 eyes, 6 patients). Laser prophylaxis was utilized in 69% of patients with Type I and 85% with Type II. Unilateral retinal detachment following laser prophylaxis occurred in one patient with Type I and two with Type II. All identified COL2A1 variants in the Type I cohort are expected to cause disease through haploinsufficiency, and 92% of COL11A1 variants in the Type II cohort are presumed to be in-frame and exert a dominant negative effect, consistent with historical reporting. The proportion of Types I and II Stickler syndrome are equal in our pediatric population, and patients self-identifying as Hispanic comprised the majority of Type II, supporting the need for additional study of possible under-detection of Type II in diverse populations. Our Type II cohort showed higher myopia and incidence of Pierre Robin sequence, and similar rates of retinal detachment and systemic manifestations compared to the Type I cohort. Our datasets provide important data regarding the safety and short-term effectiveness of laser prophylaxis, but larger and longer-term studies are needed, especially for those with Type II Stickler syndrome.

Due to the recent advent of gene-targeted retinal therapies, the clinical value of high-yield genetic testing for inherited retinal dystrophies (IRDs) has increased considerably. However, diagnostic yield is limited by the reported patient populations in allele frequency databases. This study aimed to determine the effect of race and ethnicity on diagnostic yield in IRDs. Retrospective review of individuals with suspected IRD based on clinical findings or diagnosis of associated syndrome who underwent genetic testing between 2009 and 2021. Self-reported race and ethnicity, ophthalmic examination findings, ERG results, and genetic testing findings were collected and analyzed. In 93 individuals (90 families) with suspected IRD, the diagnostic yield was 72% (67 individuals). The rate of diagnostic yield was not significantly associated with family history, associated syndromes, age at testing, ERG results, or ophthalmic exam findings. Further, higher rates of positive diagnostic yield were not associated with more recent genetic testing. There was a trend toward differences in diagnostic yield between races (77% White, 65% Other, 64% Asian, 50% Black) and ratio of pathogenic/likely pathogenic (P/LP) variants to variants of unknown significance (46%:54% White, 36%:64% Other, 31%:69% Asian, 30%:70% Black). Current genetic testing for IRDs trends toward higher diagnostic yield and identification of P/LP variants in patients identifying as White compared to other races. In order to prevent negative impacts on access to gene-targeted trials and treatments for non-White patients, wider genetic testing in diverse populations is required to create comprehensive catalogs of gene variants associated with IRDs.

The MAF gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the MAF variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal MAF variants and their associated congenital cataracts and ophthalmic findings were reviewed. The patient we present and his biological parents had genetic testing via a targeted gene panel followed by trio-based whole exome sequencing. A 4-year-old patient with a history of bilateral nuclear and cortical cataracts was found to have a novel, likely pathogenic de novo variant in MAF, NM_005360.5:c.922A>G (p.Lys308Glu). No syndromic findings or anterior segment abnormalities were identified. We report the novel missense variant, c.922A>G (p.Lys308Glu), in the C-terminal DNA-binding domain of MAF classified as likely pathogenic and associated with non-syndromic bilateral congenital cataracts.

MAF encodes a transcription factor involved in T-helper-2 (Th2) cell differentiation. Heterozygous pathogenic variants in MAF have been observed in both isolated and syndromic congenital cataract cases; genotype–phenotype correlations are based on the location of the variant within the gene. Variants in the N-terminus domain of MAF are associated with cataracts as part of Aymé-Gripp syndrome. The purpose of this report is to expand the ocular phenotypic spectrum of Aymé-Gripp syndrome by describing a patient with MAF variant c.185C>G, p.Thr62Arg, and the traditional systemic findings and congenital cataracts as well as an unusual feature of pigmentary retinopathy, which has not been previously reported in Aymé-Gripp syndrome. Additionally, a comprehensive review of the literature was completed to report ocular genotype–phenotype data on previously reported patients with MAF-associated Aymé-Gripp syndrome.

Introduction: Pediatric cataracts are a significant cause of vision loss in children and may present in isolation or in association with other ocular or systemic diseases. Despite advances in molecular diagnostics, the underlying etiology of cataracts in most patients remains unknown, even in the setting of a positive family history. Genetic testing for pediatric cataracts is neither standardized nor widely utilized. Lack of standardization is multifold, including limited published clinical and experimental reports and the absence of a comprehensive list of candidate genes with grading of the strength of gene-disease relationships. Areas Covered: The purpose of this review is to provide a comprehensive list of the 81 candidate genes potentially associated with non-syndromic pediatric cataracts and the accompanying case-based and experimental literature support in order to start the process of developing a standardized approach to genetic testing. Inheritance patterns, other associated ocular findings, and proposed mechanisms of pathogenesis will be described for the candidate genes. Genes that are associated with two distinct phenotypes, one syndromic and one characterized by non-syndromic cataracts, will also be presented. The types of cataracts and age of onset are often highly variable at both the gene and variant level, so they will not be the focus of this review, but are of interest for future studies. Future Work: Future work is needed to formalize a standardized list of established and candidate genes for non-syndromic pediatric cataracts and to systematically grade our confidence in the gene-disease relationships through the ClinGen framework. An improvement in genetic testing for pediatric cataracts will improve clinical care of these patients and their families regarding prognostication, personalized medical management, and clarification of recurrence risk for reproductive decision making. Further, a better understanding of the pathogenesis of pediatric cataracts can lead to targets for novel treatment development.