The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006–2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene–disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference (p = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) were most common. Further, Hermansky–Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield.

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.

In 2019, the American College of Medical Genetics and Genomics and the Clinical Genome Resource published updated technical standards for the interpretation and reporting of copy number variants (CNVs), introducing a semiquantitative classification system to improve standardization and consistency between laboratories. Evaluation of these guidelines' performance will inform laboratories about the impact of their implementation into clinical practice. A total of 145 difficult-to-classify CNVs, originally assessed by an academic molecular diagnostic laboratory, were re-interpreted/classified according to the American College of Medical Genetics and Genomics-Clinical Genome Resource guidelines. Classifications between interpretation systems were then compared. The concordance rate was 60.7%, and significantly more variants of uncertain significance were obtained when using the guidelines (n = 98) versus the laboratory's classification system (n = 49; P < 0.001). The concordance rate was presumably impacted by the intentionally unclear nature of the selected variants. The difference in variant of uncertain significance rate was largely due to laboratory-specific practices for variant interpretation and reporting and differences in utilization of general population data. Laboratory-specific policies and practices may need to be addressed for true standardization. Challenges to consistent guideline utilization are centered around the general lack of high-quality curated data available for CNV interpretations and the inherent subjectivity in the selection of evidence criteria and application of evidence points. Multiple aspects of the guidelines were highlighted to further improve classification standardization.

CHARGE syndrome is a rare multi‐system condition associated with CHD7 variants. However, ocular manifestations and particularly ophthalmic genotype–phenotype associations, are not well‐studied. This study evaluated ocular manifestations and genotype–phenotype associations in pediatric patients with CHARGE syndrome. A retrospective chart review included pediatric patients under 20 years‐old with clinical diagnosis of CHARGE syndrome and documented ophthalmic examination. Demographics, genetic testing, and ocular findings were collected. Comprehensive literature review enhanced the genotype–phenotype analysis. Forty‐two patients (20 male) underwent eye examination at an average age of 9.45 ± 6.52 years‐old. Thirty‐nine (93%) had ophthalmic manifestations in at least one eye. Optic nerve/chorioretinal colobomas were most common (38 patients), followed by microphthalmia (13), cataract (6), and iris colobomas (4). Extraocular findings included strabismus (32 patients), nasolacrimal duct obstructions (11, 5 with punctal agenesis), and cranial nerve VII palsy (10). Genotype–phenotype analyses (27 patients) showed variability in ocular phenotypes without association to location or variant types. Splicing (10 patients) and frameshift (10) variants were most prevalent. Patients with CHARGE syndrome may present with a myriad of ophthalmic manifestations. There is limited data regarding genotype–phenotype correlations and additional studies are needed.

The CYP1B1 gene encodes a cytochrome p450 monooxygenase enzyme, and over 150 variants have been associated with a spectrum of eye diseases, including primary congenital glaucoma, anterior segment dysgenesis, juvenile open-angle glaucoma, and primary open-angle glaucoma. Clinical genetics has yielded insights into the functions of the various CYP1B1 gene domains; however, animal studies are required to investigate the molecular role of CYP1B1 in the eye. While both zebrafish and mice express CYP1B1 in the developing eye, embryonic studies have shown disparate species-specific functions. In zebrafish, CYP1B1 regulates ocular fissure closure such that overexpression causes a remarkable phenotype consisting of the absence of the posterior eye wall. Adult CYP1B1 null zebrafish lack an ocular phenotype but show mild craniofacial abnormalities. In contrast, CYP1B1^−/− mice display post-natal mild to severe trabecular meshwork degeneration due to increased oxidative stress damage. Interestingly, the retinal ganglion cells in CYP1B1 null mice may be more susceptible to damage secondary to increased intraocular pressure. Future studies, including detailed genotype–phenotype information and animal work elucidating the regulation, substrates, and downstream effects of CYP1B1, will yield important insights for developing molecularly targeted therapies that will aim to prevent vision loss in CYP1B1-related eye diseases.

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.