Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

Tanner, Alexander; Chan, Hwei Wuen; Schiff, Elena; Mahroo, Omar A.; Pulido, Jose S.

doi:10.1136/bmjophth-2022-001079

Cited by 5 publications

(12 citation statements)

References 45 publications

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“…Many ocular tumour-associated-genes, when haploinsufficient, are strongly associated with negative selection. In contrast, we have previously shown that for IRDs, relatively few genes were associated with negative selection for loss of function variants 9. It should be noted that many of these ocular tumour-associated-genes develop their mutations as somatic mutations.…”

Section: Discussionmentioning

confidence: 76%

Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population

Tanner,

Sagoo,

Mahroo

et al. 2024

BMJ Open Ophth

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BackgroundLarge genomic databases enable genetic evaluation in terms of haploinsufficiency and prevalence of missense and synonymous variants. We explored these parameters in ocular tumour-associated genes.MethodsA curated list of ocular tumour-associated genes was assessed using the genomic databases Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) and compared with breast and lung cancer-associated gene lists. Haploinsufficiency was determined based on specific criteria: probability of loss of function index ≥0.9 in gnomAD, upper CI O/E limit <0.35 for loss of function variants in gnomAD and/or a DECIPHER pHaplo ≥0.86. UniProt was used for further gene characterisation, and gene ontology Protein Analysis THrough Evolutionary Relationships was explored for common biological pathways. In addition, we identified genes with under-representation/over-representation of missense/synonymous variants.ResultsFifty-seven genes were identified in association with ocular and extraocular tumours.Regarding haploinsufficiency, 41% of genes met the criteria for negative selection, with 57% categorised as tumour-suppressing and 39% as oncogenic. Most genes were involved in regulatory processes. Regarding triplosensitivity, 33% of genes reached significance and 83% of these were haploinsufficient. Analysis of variants revealed under-representation of missense variants in 23% of genes and over-representation of synonymous variants in 5% of genes. Ocular tumour-associated genes exhibited higher scores for haploinsufficiency and triplosensitivity compared with breast and lung cancer-associated genes. Pathway analysis revealed significant enrichment in cellular proliferation, differentiation and division. Encoded proteins of ocular tumour-associated genes were generally longer than the median of the UniProt database.ConclusionOur findings highlight the importance of negative selection in ocular tumour genes, supporting cranial gene conservation. This study provides insights into ocular tumourigenesis and future research avenues.

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Section: Discussionmentioning

confidence: 76%

Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population

Tanner,

Sagoo,

Mahroo

et al. 2024

BMJ Open Ophth

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“…Haploinsu ciency in PRPF31 is a well-established mechanism in the pathogenesis of RCD [20], [21] , [22]. The majority of PRPF31 mutations result in null alleles, leading to haploinsu ciency and subsequent photoreceptor death in the retina [20], [21]. This mechanism is responsible for the incomplete penetrance of the disease phenotypes associated with PRPF31 variations [20].…”

Section: Discussionmentioning

confidence: 99%

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Mousawi,

Choukeir,

Jaffal

et al. 2024

Preprint

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Background and Objectives: Rod-cone dystrophy (RCD), also known as Retinitis Pigmentosa, is the most common group of retinal dystrophies, affecting around 1:4,000 individuals worldwide. Herein, our objective was to identify the genetic cause of RCD in two Lebanese families with distinct inheritance patterns and explore the potential role of PRPF31 haploinsufficiency. Methods The study combined next-generation sequencing, real-time PCR (qPCR), and chromosomal microarray to identify, validate, and delineate the causative copy number variations (CNVs) identified in both families of this study. gene expression analysis using qPCR and Western Blot were conducted to assess the PRPF31 variant's impact on gene expression levels. Results A novel heterozygous deletion (701 bp) spanning exons 6 and 7 of PRPF31 was identified in the first family (F11), leading to autosomal dominant RCD through haploinsufficiency, evidenced by reduced mRNA and total absence of protein expression levels in the affected individuals (F11:III.2 and F11:II.1). A rare previously reported homozygous deletion in MERTK was found in the second family (F26), causing autosomal recessive RCD. These findings highlight the diversity of CNVs contributing to RCD and the critical role of haploinsufficiency in autosomal dominant RCD pathogenesis. Conclusion The current study expands the mutational spectrum associated with PRPF31 and MERTK genes in RCD, underscoring the importance of CNVs in its etiology. Identifying haploinsufficiency as a disease mechanism in PRPF31-related autosomal dominant RCD represents a stepping stone for future analyses regarding gene augmentation therapies.

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“…Tissue-specific RAE and BAE thresholds were defined using the same Z-score cutoff for body tissue and brain tissue. Loss-of-function intolerance was determined by cross-referencing our dataset with the dataset from Tanner et al, 2022 [8]. We evaluated the molecular and biological pathways that are significantly enriched using the GO knowledgebase (http://geneontology.org/, accessed on 7 July 2023) (http://pantherdb.org/, accessed on 7 July 2023) for both hc-BAE and hc-RAE genes [9,10].…”

Section: Methodsmentioning

confidence: 99%

“…Recent work has developed new methods to reveal RAE genes and has generated large, open-source datasets of RAE and biallelic expression (BAE) genes [7]. Our study used this dataset, in concert with other datasets [8] and publicly available genetics resources, including the Gene Ontology (GO) knowledgebase [9,10], to define the roles of RAE and BAE among IRDs.…”

Section: Introductionmentioning

confidence: 99%

Random Allelic Expression in Inherited Retinal Disease Genes

Richards,

Pulido

2023

CIMB

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Inherited retinal diseases (IRDs) are a significant contributor to visual loss in children and young adults, falling second only to diabetic retinopathy. Understanding the pathogenic mechanisms of IRDs remains paramount. Some autosomal genes exhibit random allelic expression (RAE), similar to X-chromosome inactivation. This study identifies RAE genes in IRDs. Genes in the Retinal Information Network were cross-referenced with the recent literature to identify expression profiles, RAE, or biallelic expression (BAE). Loss-of-function intolerance (LOFI) was determined by cross-referencing the existing literature. Molecular and biological pathways that are significantly enriched were evaluated using gene ontology. A total of 184 IRD-causing genes were evaluated. Of these, 31 (16.8%) genes exhibited RAE. LOFI was exhibited in 6/31 (19.4%) of the RAE genes and 18/153 (11.8%) of the BAE genes. Brain tissue exhibited BAE in 107/128 (83.6%) genes for both sexes. The molecular pathways significantly enriched among BAE genes were photoreceptor activity, tubulin binding, and nucleotide/ribonucleotide binding. The biologic pathways significantly enriched for RAE genes were equilibrioception, parallel actin filament bundle assembly, photoreceptor cell outer segment organization, and protein depalmitoylation. Allele-specific expression may be a mechanism underlying IRD phenotypic variability, with clonal populations of embryologic precursor cells exhibiting RAE. Brain tissue preferentially exhibited BAE, possibly due to selective pressures against RAE. Pathways critical for cellular and visual function were enriched in BAE, which may offer a survival benefit.

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Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

Cited by 5 publications

References 45 publications

Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population

Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Random Allelic Expression in Inherited Retinal Disease Genes

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