Institute of Genetic Medicine

Staff Profile

Professor Joris Veltman

Director

Background

Director of the Institute of Genetic Medicine at Newcastle University

Professor of Translational Genomics

Royal Society Wolfson Research Merit Award Holder




Research

How is it possible that severe early-onset disorders are mostly genetic in origin, even though the disorders are not inherited because of their effect on fitness? Our research using state-of-the-art genomics approaches in patient-parent trios have recently indicated that most of these disorders are caused by de novo germline mutations, arising mostly in the paternal lineage.   

My research has contributed significantly to the understanding of mutational mechanisms underlying severe genetic disorders and to the implementation of genomics approaches in medicine. Early on in my career, my research using genomic microarrays enhanced our understanding of structural genomic variation and its role in intellectual disability and rare syndromes. Following this success we were the first in the world to implement genomic microarrays in diagnostics. More recently, our research using both exome and genome sequencing has provided strong experimental evidence for a de novo paradigm in severe early-onset disorders. We could show that de novo germline mutations, detected by comparing exomes or genomes of patients to that of their unaffected parents, are the major cause of severe intellectual disability. Following this success we implemented exome sequencing in diagnostics in 2011. Last year, diagnostic exome sequencing was performed in more than 5000 patients in Nijmegen. Currently, we are performing clinical utility studies to determine whether we should replace this by genome sequencing. Application of this ultimate genetic test in our research allowed us to start understanding mutational processes and establish links between the occurrence and frequency of these mutations and risk factors. Most notably, work by others and us has clearly demonstrated that advanced paternal age is a risk factor for severe genetic disorders in the offspring.

Since our first publication on the detection of de novo mutations in intellectual disability in 2010, I have focused my research on further understanding the frequency, generation, risk factors and role of these de novo mutations in genetic disease. Specifically, my group and I have moved from studying de novo mutations in the coding region to studying the entire genome. This has provided insight into the presence and role of the different types of de novo mutations in the genome of patients with intellectual disability, from single point mutations to structural rearrangements. Also, we obtained insight into the paternal origin of de novo germline mutations and identified parent-of-origin-specific mutation signatures becoming more pronounced with increased parental age, pointing to different mutational mechanisms in spermatogenesis and oogenesis. Furthermore, we optimized and applied highly sensitive single molecule Molecular Inversion Probe (smMIP) technology to distinguish germline from somatic de novo mutations. This allowed us to demonstrate that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited from a low-level mosaicism in one of the parents. In the last 2 years I have started to focus my research on the role of de novo mutations in male infertility. For this I have established local, national and international collaborations, obtained informed consent, collected patient samples and hired personnel. We have started the first pilot studies by performing targeted smMIP approaches in 1000 men with unexplained male infertility. In addition, we have started RNA sequencing pilot studies in germ cell populations from FACS sorted testis biopsies of fertile and infertile men.

Publications