Integrative omics approaches to advance rare disease diagnostics

Abstract

Over the past decade high‐throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity, and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease‐causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA‐sequencing, proteomics, metabolomics and DNA‐methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.This article is protected by copyright. All rights reserved.

Molecular mechanisms of human overgrowth and use of omics in its diagnostics: chances and challenges

“…Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven interpretation of molecular and physiological data. Currently, the routine clinical, biochemical and molecular testing approaches and the interpretation of their results often run in parallel, but future approaches require the comprehensive AI-based integration of these datasets ( Smirnov et al, 2023 ).…”

“…However, several of the omic approaches (e.g., long-read technologies) are currently under development or applied in research and clinical study settings ( Figure 2 ) ( Smirnov et al, 2023 ).…”

“…Thus, the main application of episignature testing is the functional evaluation of genomic variants in the specific genes and classification of variants of unknown significance in these factors. In contrast to imprinting disorders where the molecular diagnostic testing addresses the disease-specific loci, episignatures are determined by running epigenome-wide assays (i.e., array, whole genome-wide bisulphite sequencing) ( Mannens et al, 2022 ; Smirnov et al, 2023 ). The underlying disturbance affects genes which encode proteins of the epigenetic machinery, and for several disorders highly specific epigenetic patterns have been reported.…”

SSIEM 2022 Annual Symposium in Freiburg, Germany

“…5 Holger Prokisch presented multiomics pipelines as a tool to improve understanding of variant pathogenicity in mitochondrial disorders as outlined in his article "Integrative omics approaches to advance rare disease diagnostics". 6 In Epigenetics meets genetics, the role of clinical epigenomics in the diagnosis of metabolic diseases was outlined and environmental factors that might play an important role in this scenario were discussed. After Genetics and Environment, Epigenetics was considered the third dimension of phenotypic variation and disease risk.…”

“…Henna Tyynisma reviewed how genetics changed the face of mitochondrial disease and demonstrated disease models of mitochondrial aminoacyl‐tRNA synthetase defects 5 . Holger Prokisch presented multiomics pipelines as a tool to improve understanding of variant pathogenicity in mitochondrial disorders as outlined in his article “Integrative omics approaches to advance rare disease diagnostics” 6 …”