Prof. Han Brunner

 

Henri Gerrit (Han) Brunner (MD, PhD),
Professor of Human Genetics at  Radboud University Nijmegen Medical Center, and Maastricht University Medical Center, the Netherlands.

Han Brunner is full professor and head of the department of Human Genetics at Nijmegen University Hospital, and  at Maastricht University Medical Center, in the Netherlands.
Han Brunner discovered a large number of disease genes, by applying cutting-technologies (genomic microarrays, exome sequencing, and whole genome sequencing) to understand genetic diseases. Much of this work is on neurodevelopmental conditions such as intellectual disability and abnormal behaviour. His work has established  that in non-consanguineous populations, the major cause of intellectual disability lies in spontaneous new mutations. Han Brunner received a number of international awards for his work in translating novel research findings into patient diagnosis and care. He is an elected member of the Academia Europea and of the Royal Netherlands Academy of Arts and Science.

 

Abstract
Genomic sequencing in neuroscience

Han G. Brunner, Department of Clinical Genetics MUMC+ and department of Human Genetics, Radboudumc. Han.Brunner@MUMC.nl

Genome sequencing is a generic technology with myriad applications. It can sequence the germ-line genome in genetic disease, the somatic genome in cancer. Genome sequencing can also show genome function at the tissue and cellular level, either by monitoring  epigenome states (by AtacSeq or methylome), or by reading gene activity by sequencing RNA of cells and tissues. Finally, sequencing can be used to barcode cells, and trace their behaviour in development, or in experiments involving functional read-outs.

We have used genomic sequencing to study intellectual disability for the last 10 years. We find that most severe handicaps are due to new mutations. New mutations can occur in specific genes or to rearrangements involving larger chromosomal segments called CNVs. This means that intellectual disability is largely a problem of random events. The only known strong risk factor is age.

We also find, that every individual carries almost 3 deleterious recessive alleles. This means that 1.5% of the outbred population, and 35% of consanguineous first-cousin couples are at 25% risk of recessive diseases such as deafness, blindness, intellectual disability and others. We can now see at the individual level, who carries these hidden recessive genetic alleles. In the case of high-risk first cousins, we can offer a preconception carrier test. If the couple is found to be at 25% genetic risk they can then choose either to have a prenatal test in pregnancy, or a preimplantation genetic test after fertilization to select an IVF-embryo that does not carry both alleles.

Current genome sequencing technology has a number of weaknesses. These are a reflection of the technology which relies on sequencing short (100base-pair) fragments generated by PCR, that are subsequently pieced together using bioinformatic algorithms. As a consequence, genes with repeats or pseudogenes, and CG-rich regions are not well-represented. This missing sequence is sometimes referred to as the “dark matter” of the genome. Also, certain structural rearrangements are not visible to the technology. New technology is now reaching the market that can address these issues. The most promising are long-read sequencing technology to improve mapping, and PCR-free technology to reduce errors. Other machines allow the detection of various classes of structural rearrangements. Other long-read applications are in transcriptomics to detect changes in RNA isoforms, that may reflect a different functional cellular state.