Epigenomic Approaches for the Diagnosis of Rare Diseases

Abstract

Rare diseases affect more than 300 million people worldwide. Diagnosing rare diseases is a major challenge as they have different causes and etiologies. Careful assessment of clinical symptoms often leads to the testing of the most common genetic alterations that could explain the disease. Patients with negative results for these tests frequently undergo whole exome or genome sequencing, leading to the identification of the molecular cause of the disease in 50% of patients at best. Therefore, a significant proportion of patients remain undiagnosed after sequencing their genome. Recently, approaches based on functional aspects of the genome, including transcriptomics and epigenomics, are beginning to emerge. Here, we will review these approaches, including studies that have successfully provided diagnoses for complex undiagnosed cases.

Integrative omics approaches to advance rare disease diagnostics

“…Epigenetic modifications, such as DNA methylation and histone modifications, have been extensively studied and have been shown to play a critical role in the development and manifestation of several rare diseases 130 . In recent years, the detection of DNA methylation episignatures has gained the most popularity among epigenetic approaches for rare disease diagnosis.…”

“…Epigenetic modifications, such as DNA methylation and histone modifications, have been extensively studied and have been shown to play a critical role in the development and manifestation of several rare diseases. 130 In recent years, the detection of DNA methylation episignatures has gained the most popularity among epigenetic approaches for rare disease diagnosis. Several studies have shown that pathogenic variants in disease-causing genes can induce stable changes in DNA methylation patterns at multiple positions across the genome, referred to as episignatures.…”

Un protocolo para el análisis de los problemas de lenguaje en las enfermedades raras

“…Una alternativa consiste en determinar posibles cambios en la regulación de la expresión génica debido a otros mecanismos moleculares, en particular, a la metilación, que es una modificación de la molécula de ADN, generalmente transitoria, que tiene como objeto disminuir o anular por completo la expresión de genes concretos. Se conocen muchas enfermedades raras causadas por cambios epigenéticos (Martínez-Delgado y Barrero, 2022;Fu et al, 2023) y en particular, numerosos trastornos cognitivos resultantes de una metilación anómala de determinados genes o bien, de la mutación de genes responsables de la metilación del ADN (Gräff and Mansuy, 2009;Kim et al, 2017;Aref-Eshgi et al, 2020). Un análisis del metiloma (esto es, del estado de metilación del genoma) permite detectar zonas en las que los genes se estén expresando en mayor medida de lo habitual (por estar hipometiladas) o en menor proporción de lo que lo están en los sujetos neurotípicos (por estar hipermetiladas), lo que puede ayudar a identificar las posibles causas moleculares de una enfermedad rara cuando no se han detectado mutaciones puntuales (mediante el WES o, incluso, el estudio del genoma completo) o CNVs (mediante microarrays estructurales).…”

Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology

“…Rare diseases affect more than 300 million patients worldwide [1]. Inborn errors of metabolism disorders (IEMs) are a group of over 1000 heterogeneous disorders, and although most disorders are orphan diseases, IEMs are collectively frequent [2,3].…”