Exome sequencing identifies existing and novel variants in a South African cohort presenting with anterior segment dysgenesis

Gene, Journal Year: 2025, Volume and Issue: unknown, P. 149273 - 149273

Published: Jan. 1, 2025

Anterior segment dysgenesis (ASD) defines a collection of congenital eye disorders that affect structures within the anterior eye. Mutations in genes initiate and regulate complex pathways involved development can cause spectrum such as ASD, cataracts corneal opacity. In South Africa, causes ASD are poorly understood with few studies looking at possible genetic basis for these disorders. this study, we performed exome sequencing on cohort African patients focusing panel known to pathways, including PXDN gene which has recently been associated ASD. We identified novel well established variants: specifically, found disease-causing variant PAX6; variants likely be pathogenic GJA8, BCOR EPHA2, uncertain significance LTBP2. conclusion, study is first show presenting identification highlights need expand upon understudied populations.

Language: Английский

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Insights into CYP1B1-Related Ocular Diseases Through Genetics and Animal Studies

Life, Journal Year: 2025, Volume and Issue: 15(3), P. 395 - 395

Published: March 3, 2025

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

Language: Английский

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Investigating a possible role of R3HCC1L in embryonic development and ocular disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Abstract Peters anomaly (PA) is an anterior segment ocular disorder with wide phenotypic variability and genetic heterogeneity. Here we report a family consisting of male diagnosis syndromic PA his unaffected parents, no causative variants identified in known developmental genes. Exome sequencing analysis compound heterozygous missense variants, c. 1022A>T p.(Asp341Val) c.1457T>A p.(Phe486Tyr), R3HCC1L . Both are ultra-rare control populations have CADD scores 21.9 23.3, respectively, suggesting possible deleterious effects. The transcript encode three different protein isoforms all sharing two conserved C-terminal domains, RNA recognition motif (RRM) coiled-coil domain (CCD), likely represent RNA-binding involved post-transcriptional gene regulation; the patient located within N-terminal part shared by isoforms, upstream RRM CCD domains. To investigate role embryonic development, single zebrafish ortholog R3HCC1L, r3hcc1l , was examined for its expression function. In situ studies showed that expressed developing lens, cornea, retina hyaloid vasculature, supporting development vertebrates. CRISPR-Cas9 editing used to generate line 4-bp deletion c.623-626del, predicted result nonsense-mediated decay and, if expressed, nonfunctional truncated (p.Thr208fs*39) lacking 80% entire CCD. resultant c 623-626del homozygous animals did not show any visible structural abnormalities eye or other systems, normal survival genotypes adulthood, providing support congenital phenotype interest. However, function may be completely human and/or compensatory mechanisms present humans. addition, engineered variant disrupts most region R3HCC1L/r3hcc1l leads complete loss-of-function this gene, which from disease mechanism associated specific alleles patient. Finally, while it important consider limitations animal models, also necessary highlight observed Identification new interest families affected phenotypes, successful, will provide further gene.

Language: Английский

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Potential Involvements of Anterior Segment Dysgenesis-Associated Genes in Primary Congenital Glaucoma

Seminars in Ophthalmology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 10

Published: Dec. 9, 2024

Background The anterior segment of the eye plays a crucial role in maintaining normal intraocular pressure and vision. Developmental defects structures lead to dysgenesis (ASD) primary congenital glaucoma (PCG), which share overlapping clinical features. Several genes have been mapped characterized ASD, some are also involved other phenotypes. PCG exhibits genetic heterogeneity like but known do not account for entire basis disease. Considering significant phenotypic genotypic overlap between ASD PCG, this article explores possible involvements ASD-associated pathogenesis.

Language: Английский

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Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease

Genes, Journal Year: 2024, Volume and Issue: 15(12), P. 1636 - 1636

Published: Dec. 20, 2024

Background: Disruption of HCCS results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia/anophthalmia, corneal opacity, aplastic lesions, variable central nervous system and cardiac anomalies, intellectual disability, poor growth heterozygous females. Structural variants consisting chromosomal rearrangements or deletions are the most common variant type, but a small number intragenic have been reported. Methods: Exome sequencing identified affecting HCCS. Results: Three novel two genomic were found individuals primarily ocular features MLS. X-inactivation was highly skewed affected all three variants. Corneal opacity penetrant feature (100%). In addition, duplication uncertain significance including both AMELX male glaucoma, an atrial septal defect, enamel hypoplasia along family history developmental disorders consistent X-linked inheritance. Conclusion: Although expressivity is known MLS, our findings provide additional support for testing isolated anomalies further evidence its association congenital aphakia, aniridia/other iris defects, staphyloma/ectasia.

Language: Английский

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Further Evidence for a Possible Role for ZHFX4 in Human Ocular Development and Disease

American Journal of Medical Genetics Part A, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

The data that support the findings of this study are openly available in ClinVar at https://www.ncbi.nlm.nih.gov/clinvar/.

Language: Английский

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