A scoping review and proposed workflow for multi-omic rare disease research

Abstract

Background: Patients with rare diseases face unique challenges in obtaining a diagnosis, appropriate medical care and access to support services. Whole genome and exome sequencing have increased identification of causal variants compared to single gene testing alone, with diagnostic rates of approximately 50% for inherited diseases, however integrated multi-omic analysis may further increase diagnostic yield. Additionally, multi-omic analysis can aid the explanation of genotypic and phenotypic heterogeneity, which may not be evident from single omic analyses. Main body: This scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Additionally, The Cancer Genome Atlas publications were searched for relevant studies and forward citation searching / screening of reference lists was performed to identify further eligible articles. Following title, abstract and full text screening, 66 articles were found to be eligible for inclusion in this review. Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The average age of participants (where known) across studies was 39.4 years. There has been a significant increase in the number of multi-omic studies in recent years, with 66.7% of included studies conducted since 2016 and 33% since 2018. Fourteen combinations of multi-omic analyses for rare disease research were returned spanning genomics, epigenomics, transcriptomics, proteomics, phenomics and metabolomics. Conclusions: This scoping review emphasises the value of multi-omic analysis for rare disease research in several ways compared to single omic analysis, ranging from the provision of a diagnosis, identification of prognostic biomarkers, distinct molecular subtypes (particularly for rare cancers), and identification of novel therapeutic targets. Moving forward there is a critical need for collaboration of multi-omic rare disease studies to increase the potential to generate robust outcomes and development of standardised biorepository collection and reporting structures for multi-omic studies.

The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

“…Linkage analysis with candidate gene screening dominated the discovery of SCD genes in the past, often thanks to prior knowledge of these genes’ functions and expression profiles, their products, the pathways they serve, or pertinent animal models. WES is now dominating SCD gene discovery and we can expect that WGS will dominate the discovery of the genes causing Mendelian diseases in the future, probably within integrated multi-omics strategies to reduce the number of candidate variants ( Posey, 2019 ; Kerr et al, 2020 ).…”

“…A holistic approach that integrates data obtained from multiple omics layers (multi-omics approach) has a higher biological reliability and can substantially enhance new Mendelian genes’ discovery than the single-omics approaches ( Labory et al, 2020 ). The multi-omics have been successfully used in many diseases, including neurological diseases, and is thus a promising approach to enhance the discovery of new SCD genes ( Crowther et al, 2018 ; Kerr et al, 2020 ; Labory et al, 2020 ).…”

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

“…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 ).…”

“…Emerging evidence for epigenetic phenomena has transformed investigations of heritable influences on disease and, complementary to genome-wide association studies (GWAS), it is now cost-effective to perform population-based studies of the epigenome (Rakyan et al, 2011b;Canadas-Garre et al, 2018;Kato and Natarajan, 2019;Kerr et al, 2020). Epigenetic modifications modulate gene expression without changing the DNA sequence; these may be either stably inherited or dynamic epigenetic marks.…”

A proof-of-concept study of extracting patient histories for rare/intractable diseases from social media

“…The lack of patient information available for research seriously hinders the diagnosis and treatment of rare and intractable diseases [7]. In general, RD patients suffer from very severe and heterogeneous symptoms and remain undiagnosed for several years [8]. Consequently, these disease communities use social media platforms to try to find other patients with similar health problems or expertise about their rare condition, sharing manifold types of information-including symptoms, treatments, side effects, and other diseases and activities-that go beyond what is normally captured in a clinical setting or patient registry [9].…”