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Will next‐generation sequencing also take us to the next level of understanding disease mechanisms?

The advent of next-generation sequencing (NGS) led to a dramatic increase in the pace of discovery of novel rare disease-causing genes. In 2012 alone, more than 130 new pathogenic genes were identified by whole-exome sequencing (WES). In coming years the rate of new discoveries will likely rise further as NGS becomes cheaper and more widely available. In a recent article in Science, Novarino et al. added a further 18 previously unknown genes to this ever-growing list. They used WES to identify the genetic causes of autosomal recessive hereditary spastic paraplegia (HSP) in families with documented consanguinity. Screening 93 individuals in this cohort and confirming their results in further groups of patients with HSP, they discovered 15 new genes with a wide spectrum of clinical phenotypes. To elicit the potential role of these genes in the disease process, functional testing was performed across multiple human tissues as well as with knockdown modeling in zebrafish. They then went on to create an HSPome, a network containing all known and candidate genes as well as proximal interactors. This HSPome was used to identify HSP-relevant pathways and genes, which led not only led to the identification of 3 further genes but also to the discovery of several major modules involved in the pathophysiology of HSP. These included the endoplasmic reticulum (ER) and ER-associated degradation pathways as well as endosome and membrane trafficking. Other newly identified genes encode proteins involved in nucleotide metabolism and cell signaling. The researchers found links between HSP and other neurodegenerative diseases, because there was a significant overlap of HSP genes with sets of genes previously described in other neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease). This article demonstrates the breathtaking advances that have been made in this field in recent years: The development of NGS facilitates the identification of many more disease-causing genes, particularly in rare disorders. It also highlights the prospect of gaining more insight into the pathophysiology of these diseases, made possible with this new technology. However, when this improved understanding of disease mechanisms will translate to improved therapies remains to be seen.