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Publications of the Week

Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia

By April 29, 2019May 6th, 2019No Comments

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This week we profile a recent publication in the American Journal of Human Genetics from the laboratory of
Dr. James Bennett (pictured) at Seattle Children’s Research Institute.

Can you provide a brief overview of your lab’s current research focus?

Dr. Bennett’s research is focused on the genetics of congenital malformations and developmental disorders in children. More specifically, the Bennett lab is interested in “post-zygotic” mutations that arise after the single cell zygote stage, and are not present in every cell in the body. These mutations are more difficult to detect, and a central hypothesis of the lab is that these types of mutations represent an under-recognized source of human genetic variation. His lab uses cutting-edge next generation DNA sequencing methods to identify these types of mutations and determine their significance in human development. One area of particular focus is congenital vascular malformations, a large number of which have been shown to be due to post-zygotic, activating mutations in genes better known for their role in cancers.

In addition to his research on post-zygotic mutations, Dr. Bennett also spends time seeing patients in pediatric genetics clinics, with a particular interest in children with vascular malformations. He is also co-director of the Seattle Children’s Hospital Molecular Diagnostic lab, where he is focused on diagnosis using next generation sequencing and other DNA sequencing methods.

What is the significance of the findings in this publication?

Most generally, this shows how much can be learned from a single patient with a rare disease. More specifically:

  1. It is the first pathological description of a human brain without microglia.
  2. It expands phenotypes associated with mutations in CSF1R to pediatric onset conditions, demonstrating how we still do not know all of the phenotypes that can be associated with a gene, even for fairly well known genetic conditions.
  3. We developed a zebrafish genetic model to understand mechanisms underlying agenesis of the corpus callosum.

What are the next steps for this research?

A better understanding of the mechanisms underlying how CSF1R deficiency leads to these brain malformations is needed. Microglia play a primary role in brain development, and are not just “bystanders” as taught in medical school. The details of this primary role in brain development remain unclear, however. It also remains unclear why and how heterozygous CSF1R mutations lead to the adult-onset condition, ALSP. What happens to microglia between birth and the development of neurodegenerative symptoms (usually in the 4th decade of life) is unclear. My collaborator, Dr. Tjakko Van Ham, is using his fish model as well as studying human brains to address some of these issues.

This research was funded by:

Dr. Bennett currently is the recipient of the Arnold Lee Smith Endowed Professorship for Research Faculty Development in the Department of Pediatrics, and a Burroughs Wellcome Fund Career Award for Medical Scientists.

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