Mendelian diseases, such as cystic fibrosis and thalassemia, are defined to be caused by mutations present in a single gene, which yield a series of distinct physiological symptoms and influence the underlying pathogenesis of these disorders. Each of these diseases allows for a relatively straightforward diagnosis based on traditional genetic testing methods. However, significant advancements in the field of next-generation sequencing (NGS) and the sophisticated analysis of genetic data have catalysed a paradigm shift from a single-gene focus to a more comprehensive multigene analysis. This month’s recommended paper “* indeed, “A retrospective study on clinical exome sequencing in unclear genetic disorders“ reminds us that numerous diseases are not to be not solely attributable to a singular genetic mutation, but instead to complex interactions amongst several genes, leading to multifactorial phenotypes that are more challenging to diagnose.
The variability of NGS-based diagnosis can be attributed to several factors, including the allelic complexity of the disease being investigated and the inherent diversity amongst patient populations. These nuances highlight the need for the implementation of precision medicine, which seeks to tailor diagnostic and therapeutic strategies according to the genetic and phenotypic nuances of individual patients. In response, researchers have retrospectively proposed a multigenic enriched analysis, specifically designed to broaden the diagnostic process by thoroughly exploring data derived from Clinical Exome Sequencing (CES).
The study focused on conditions characterised by autoinflammation and immunological dysregulation, which often present substantial phenotypic variability amongst affected individuals; given this variability, these conditions were prime candidates for a multigenic diagnostic approach. The aim was to observe the patterns of upregulation and downregulation of a carefully selected subset of genes, through a process known as gene set enrichment analysis. The genes selected for this analysis were chosen based on several criteria: their established likelihood of being pathogenic, their classification as variants of unknown significance, their pattern of autosomal dominant inheritance, and their low minor allele frequency.
The results of this comprehensive analysis successfully pinpointed genes that are implicated in immunological dysregulation, including ATN1, CABIN1, IRF8, KLF1, and SIRT1. These genes encode proteins that play crucial roles in modulating inflammatory responses through various post-translational modifications, thereby influencing the overall inflammatory landscape within the affected individual. This detailed examination did not only highlight the genetic causes of the diseases studied but also explained how alterations in metabolic pathways and protein-protein interactions contribute to the pathology of these conditions. The findings from this study provide essential insights that can guide therapeutic interventions, paving the way for more targeted and effective treatment strategies tailored to the unique genetic profiles of patients suffering from these complex disorders.
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* Chetta, M., Tarsitano, M., Rivieccio, M., Oro, M., Cammarota, A., De Marco, M., Marzullo, L., Rosati, A., & Bukvic, N. (2024b). A Copernican revolution of multigenic analysis: A retrospective study on clinical exome sequencing in unclear genetic disorders. Computational and Structural Biotechnology Journal, 23, 2615–2622.
