Biomedical subjects

Gavin Arno

Publications and source records attributed to Gavin Arno.

5 recordsLinked to original sources

PubMed2026

Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series.

Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.

Journal Article↗

PubMed2026

XXYLT1 and Mendelian Retinal Dystrophy.

IMPORTANCE: Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. OBJECTIVE: To leverage a GWAS for the discovery of IRD-associated genes. DESIGN, SETTING, AND PARTICIPANTS: This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. MAIN OUTCOMES AND MEASURES: The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. RESULTS: This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

Humans↗

PubMed2025

Sex Distributions in the Most Frequent Autosomal Genetic Causes of Retinitis Pigmentosa.

PURPOSE: The purpose of this study was to explore whether sex imbalances are detectable in the most frequent genetic causes of retinitis pigmentosa (RP). METHODS: Databases from centers in three countries (Moorfields Eye Hospital, London; Hospital for Sick Children, Toronto; and Australian Inherited Retinal Disease Registry, Perth, Australia) were searched, quantifying numbers of male and female patients with disease attributed to variants in the six most frequently involved autosomal RP genes. Proportions of female patients (with 95% confidence intervals [CIs]) were calculated for each gene. Two-tailed binomial testing was performed (Bonferroni corrected threshold, P = 0.008) to investigate whether proportions differed significantly from an underlying male:female ratio of 1:1. For genes where the 95% CI did not include 50%, sex distributions were also explored in previously published cohorts. RESULTS: Our search yielded 1454 patients with disease attributable to variants in USH2A (n = 550), RP1 (n = 277), RHO (n = 246), PRPF31 (n = 158), EYS (n = 124), and MYO7A (n = 99). Proportions of female patients (95% CI) for each gene were 46.2% (42.0-50.5%), 49.5% (43.4-55.5%), 55.3% (48.8-61.6%), 63.9% (55.9-71.3%), 39.5% (31.0-48.7%), and 42.4% (32.7-52.8%), respectively. The 95% CI did not include 50% for PRPF31 and EYS; binomial testing revealed P values of 6.24 × 10-4 and 0.025, respectively. Combining with data extracted from previously published cohorts yielded P values of 1.62 × 10-6 and 0.0084, respectively. CONCLUSIONS: We observed a significant preponderance of female patients for PRPF31-associated RP and a preponderance of male patients in those with EYS-associated RP. Our findings suggest that sex is likely to be a modifier affecting penetrance in PRPF31-associated disease and might act in the opposite direction in disease associated with EYS.

Humans↗

PubMed2025

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

PURPOSE: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Humans↗

PubMed2025

Biallelic null variants in C19orf44 cause a unique late-onset retinal dystrophy phenotype characterized by patchy perifoveal chorioretinal atrophy.

PURPOSE: To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene. METHODS: Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-polymerase chain reaction. Localization of the encoded protein in cells and in the human retina was examined by immunofluorescence staining. RESULTS: Four different pathogenic variants in C19orf44 were identified in 15 biallelic individuals from 11 unrelated families. The most common variant was c.549_550del p.(Ser185ProfsTer2). Most individuals were affected with a unique clinical phenotype characterized by late-onset patchy perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration. C19orf44 is expressed in various human tissues, including the retina, where it was found in the outer nuclear layer and in the outer plexiform layer. In cultured cells (hTERT RPE-1 and HeLa) and in human primary fibroblasts, C19orf44 is found in the nucleus, and it is downregulated during mitosis. CONCLUSION: Based on our results, C19orf44 is crucial for normal human retinal function, and pathogenic variants in this gene are associated with autosomal recessive inherited retinal disease.

Humans↗