HIGHLIGHTS
In this prospectively designed and blinded study — we demonstrate the use of long-read genome sequencing as the generic (and only!) first-tier test across all rare diseases and all genetic germline test requests performed in our diagnostics. For the first time we have an assay - that allows to consolidate ALL other germline test modalities and still provide higher diagnostic yield than all SoC tests combined. As an additional benefit, phasing, SV breakpoint accuracy and context, absolute STR lengths and motifs, and DNA methylation are automatically included in this test as well! Results show an overall diagnostic concordance between long-read genome sequencing and Soc tests of 96.4%, with long reads improving or refining diagnostic outcome in many other cases. Read all about it in the NEJM correspondence.
We are thrilled that some basic and translational studies our group were involved in, helped to push for a new diagnostic test. The Radboudumc is the first hospital in the world to implement large-scale long-read genome sequencing (lrGS) in clinical care, enabling faster and more accurate diagnoses for people with rare diseases. This new test can replace around fifteen standard-of-care genetic tests and increases the diagnostic yield by more than ten percent for some diseases. We expect that accurate lrGS will become the new global standard in diagnostics of all rare genetic diseases.
In 2024, Alex received a ZonMW (NWO) Vici grant, entitled “SOLVE-IEI: Solving Enigmas of Undiagnosed Inborn Errors of Immunity”. This enables our group to further push latest genomic innovations for an improved understanding of IEIs.
Based on an international collaborative effort, we recently described a new cause of SCID-Omenn syndrome, heterozygous (de novo) mutations in PSMB10.
As part of the Solve-RD project, we demonstrated that pan-European data re-analysis is not only feasible but also effective in diagnosing previously undiagnosed patients with rare diseases.
Alex co-edited two special issues of “Genome Research” dedicated to long-read sequencing. The respective editorials elute to these emerging technologies and insights. These special issues also included three manuscripts authored by our group.
in this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.
Spanish-Dutch research has revealed two new mutations in the TLR7 gene in healthy young men who became seriously ill with severe COVID-19. It is becoming increasingly plausible that such mutations undermine a sufficient immune response agaist SARS-CoV-2.