Systematic review of differential methylation in rare ophthalmic diseases

Kerr, Katie; McAneney, Helen; Smyth, Laura; Flanagan, Cheryl; Silvestri, Julie; Nesbitt, Micheal Andrew; Wooster, Christopher; McKnight, Amy Jayne

doi:10.1136/bmjophth-2019-000342

Cited by 4 publications

(3 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epigenetic signatures may display tissue specificity linked to disease mechanisms, however, obtaining kidney biopsy material is invasive and is not performed as part of routine clinical practice in people with DKD and T1D in the United Kingdom. Peripheral blood-based methylation biomarkers have shown promise in several clinical fields ( Moore et al, 2014 ; Agha et al, 2019 ; Cardenas et al, 2019 ; DiTroia et al, 2019 ; Henderson-Smith et al, 2019 ; Kerr et al, 2019a , b , 2020 ; Ladd-Acosta and Fallin, 2019 ; Zhou et al, 2019 ) including kidney disease ( Smyth et al, 2014b , 2018 ; Swan et al, 2015 ; Aranyi and Susztak, 2019 ; Gluck et al, 2019 ; Kato and Natarajan, 2019 ; Kerr et al, 2019b ; Park et al, 2019 ). We have previously demonstrated that blood-derived differential methylation is also reflected in kidney-derived differential methylation for CKD ( Smyth et al, 2014b ).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

Smyth

Patterson

Swan

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

A subset of individuals with type 1 diabetes will develop diabetic kidney disease (DKD). DKD is heritable and large-scale genome-wide association studies have begun to identify genetic factors that influence DKD. Complementary to genetic factors, we know that a person's epigenetic profile is also altered with DKD. This study reports analysis of DNA methylation, a major epigenetic feature, evaluating methylome-wide loci for association with DKD. Unique features (n = 485,577; 482,421 CpG probes) were evaluated in blood-derived DNA from carefully phenotyped White European individuals diagnosed with type 1 diabetes with (cases) or without (controls) DKD (n = 677 samples). Explicitly, 150 cases were compared to 100 controls using the 450K array, with subsequent analysis using data previously generated for a further 96 cases and 96 controls on the 27K array, and de novo methylation data generated for replication in 139 cases and 96 controls. Following stringent quality control, raw data were quantile normalized and beta values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls; resultant P-values for array-based data were adjusted for multiple testing. Genes with significantly increased (hypermethylated) and/or decreased (hypomethylated) levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways. Twenty-two loci demonstrated statistically significant fold changes associated with DKD and additional support for these associated loci was sought using independent samples derived from patients recruited with similar inclusion criteria. Markers associated with CCNL1 and ZNF187 genes are supported as differentially regulated loci (P < 10 −8), with evidence also presented for AFF3, which has been identified from a meta-analysis and subsequent replication of genomewide association studies. Further supporting evidence for differential gene expression in CCNL1 and ZNF187 is presented from kidney biopsy and blood-derived RNA in people with and without kidney disease from NephroSeq. Evidence confirming that methylation sites influence the development of DKD may aid risk prediction tools and stimulate research to identify epigenomic therapies which might be clinically useful for this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

Smyth

Patterson

Swan

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…54 A multiomic approach to studying disease will yield more information on inherited eye disorders than has previously been established, but as yet transcriptomics, metabolomics, proteomics and epigenomics still remain as research-based tests. 55…”

Section: Other Inheritance Patterns and Complexitiesmentioning

confidence: 99%

Practical guide to genetic screening for inherited eye diseases

et al. 2020

View full text Add to dashboard Cite

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

show abstract

“…Array-based ‘epi-signature’ testing is already clinically available for some 40 inherited conditions affecting around 60 genes (45, 46). Methylation-based studies have also suggested the causative or correlative role of aberrant methylation in diverse rare inherited conditions including Kabuki Syndrome (47), Werner Syndrome(48) rare ophthalmic disease (49), orofacial cleft (50) and fucosidosis (51), either in the presence or absence of known DNA mutations. Whether deviation from a normal methylation pattern reflects alterations of genetic or epigenetic origin, expanded methylation profiling could offer the ability to detect diagnostic signals unique to the epigenome or undetectable in DNA and RNA due to lack of measurable manifestation in those materials, or due to shortcomings in current technologies or analytical approaches.…”

Section: Introductionmentioning

confidence: 99%

Detection of outlier methylation from bisulfite sequencing data with novel Bioconductor package BOREALIS

Oliver

Jenkinson

Olson

et al. 2022

Preprint

View full text Add to dashboard Cite

DNA sequencing results in genetic diagnosis of 18-40% of previously unsolved cases, while the incorporation of RNA-Seq analysis has more recently been shown to generate significant numbers of previously unattainable diagnoses. Multiple inborn diseases resulting from disorders of genomic imprinting are well characterized and a growing body of literature suggest the causative or correlative role of aberrant DNA methylation in diverse rare inherited conditions. Therefore, the systematic application of genomic-wide methylation-based sequencing for undiagnosed cases of rare disease is a logical progression from current testing paradigms. Following the rationale previously exploited in RNA-based studies of rare disease, we can assume that disease-associated methylation aberrations in an individual will demonstrate significant differences from individuals with unrelated phenotypes. Thus, aberrantly methylated sites will be outliers from a heterogeneous cohort of individuals.Based on this rationale, we present BOREALIS: Bisulfite-seq OutlieR MEthylation At SingLe-SIte ReSolution. BOREALIS uses a beta binomial model to identify outlier methylation at single CpG site resolution from bisulfite sequencing data. This method addresses a need unmet by standard differential methylation analyses based on case-control groups. Utilizing a heterogeneous cohort of 94 rare disease patients undiagnosed following DNA-based testing we show that BOREALIS can successfully identify outlier methylation linked to phenotypically relevant genes, providing a new avenue of exploration in the quest for increased diagnostic rates in rare disease patients. We highlight the case of a patient with previously undetected hypermethylation patterns that are informing clinical decision-making. BOREALIS is implemented in R and is freely available as a Bioconductor package.

show abstract

Systematic review of differential methylation in rare ophthalmic diseases

Cited by 4 publications

References 45 publications

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

Practical guide to genetic screening for inherited eye diseases

Detection of outlier methylation from bisulfite sequencing data with novel Bioconductor package BOREALIS

Contact Info

Product

Resources

About