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Background and Clinical Significance: MSMO1, encoding a key enzyme in the cholesterol synthesis pathway, is associated with an autosomal recessive condition characterized by microcephaly, ocular abnormalities, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability. Case Presentation: This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts. Conclusions: The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation. This case expands our understanding of MSMO1 deficiency and highlights the critical role of cholesterol biosynthesis in early lens development.

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. 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 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.

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.

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.

Background/Objectives: While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in GPR143 at X: 151.56–151.59 have been shown in the literature to be associated with OA. The purpose of this study was to report the case of a Hispanic male with X-linked inherited OA associated with a hemizygous GPR143 variant and to review the literature relating to genotype–phenotype associations with GPR143 and OA. Methods: After consent to an IRB-approved protocol, a 14-year-old Hispanic male patient with OA and his parents underwent whole genome sequencing (WGS) in 2023. Two maternal uncles with nystagmus underwent targeted variant testing in 2024. A literature review of reported GPR143 variants was completed. Results: A male with reduced visual acuity, infantile-onset nystagmus, foveal hypoplasia, and iris hypopigmentation was identified to have the variant GPR143, c.455+3A>G, which was also present in his mother and two affected maternal uncles. This variant has been previously identified in other Hispanic patients of Mexican descent. Additionally, 127 variants were identified in the literature and reported to be associated with OA. All patients had reduced visual acuity (average 0.71 ± 0.23 logMAR), 99% had nystagmus, 97% foveal hypoplasia, 79% fundus hypopigmentation, and 71% iris hypopigmentation. Of those patients with reported optotype best corrected visual acuity (BCVA), eight (9%) had VA from 20/25 to 20/40, 24 (24%) had VA from 20/50 to 20/80, and 63 (67%) had VA from 20/100 to 20/200. The most frequent type of variant was missense (31%, n = 39). Frameshift and nonsense variants were associated with the lowest rates of iris hypopigmentation (50% [n = 11] and 44% [n = 8], respectively; p = 0.0068). Conclusions: This case represents phenotypic variability of GPR143-associated OA and highlights the importance of repeat genetic testing and independent analyses of test results for accurate variant classification, particularly in non-White and Hispanic patients. Further studies in more diverse populations are needed to better develop genotype–phenotype associations for GPR143-associated OA.

Pathogenic heterozygous variants in PHOX2B are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The interpretation of PHOX2B missense variation is challenging due to their rarity and the lack of available functional evidence. Consequently, most PHOX2B missense variants are classified as variants of uncertain significance (VUSs), complicating the timely diagnosis and clinical management of the condition. To generate an improved model for assessments of PHOX2B missense variants, a methodology was derived to evaluate all PHOX2B missense variants in the literature and public/private databases according to a consensus classification framework and assigned pathogenicity classifications. Pathogenicity prediction scores from the in silico prediction tools CADD, REVEL, BayesDel, and AlphaMissense were obtained for all variants. A weighted logistic regression in a multiple imputation framework was performed to assess the strength of evidence supporting application of ACMG/AMP guidelines′ PP3/BP4 criteria. CADD, REVEL, and BayesDel meet the predictive strengths for PP3/BP4 recommended by the Clinical Genome Resource (ClinGen). Based on their areas under the curve and low proportions of variants with indeterminate pathogenicity predictions, BayesDel and REVEL were the strongest predictive tools and should be utilized for routine PHOX2B missense variant assessment with this study′s calculated score thresholds for PP3/BP4 strength levels. Furthermore, the positional distribution of pathogenic and benign variants was analyzed to assess potential hotspots or critical functional domains in PHOX2B, and pathogenic variants were found to cluster in the homeodomain. The enrichment of pathogenic variation was substantiated by the prediction tools, supporting the use of the PM1 criterion for variants in the homeodomain. This calibration of existing computational prediction tools for PHOX2B missense variant classification and recognition of the homeodomain variants will enable fewer VUS classifications in favor of conclusive results, aiding in these individuals′ care.

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.

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 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.