A newly identified disorder of human brain development, with macrocephaly and impaired speech and language

06 November 2018
Some genes are especially important for regulating the development of the human brain. When a child carries a mutation disrupting one of those genes, this can lead to problems with aspects of cognitive development, including speech and language impairments. In a study published in Nature Communications, an international team of researchers and clinicians, led by scientists of the Max Planck Institute’s Language & Genetics Department, identify a new disorder of human brain development, caused by rare mutations in a gene named CHD3, and show that the mutations interfere with the way that this gene works.

Lot Snijders Blok and Simon Fisher from the Language & Genetics Department, together with the Human Genetics Department from the Radboudumc, and a team at CHU Sainte-Justine, Montréal, Canada, as well as multiple collaborators from around the world, have identified a new disorder of brain development that is caused by mutations in the CHD3 gene.

Thirty-five cases from around the world

A mutation in CHD3 in a single child with a severe speech disorder first caught the attention of the researchers two years ago. Through networks of clinical geneticists conducting next-generation DNA sequencing, they were then able to identify a total of 35 unrelated individuals from around the world, all carrying mutations of CHD3. Each of these mutations was “de novo” in the affected person, meaning that it was a newly arising gene variant present in that person but not found in her/his parents. None of these gene variants could be found occurring in large databases containing DNA sequencing data from many thousands of healthy individuals. All the mutations were predicted to affect the structure of the protein that is encoded by the CHD3 gene. This protein is thought to regulate the activities of other genes in the nervous system of embryos, affecting how brain cells move to the correct position at the right time during early development.

To define the range of clinical features of this newly discovered disorder, the clinical data of the patients with de novo CHD3 mutations were collected and systematically analyzed. It turned out that all patients had developmental delays and/or intellectual disability, although there was a surprisingly high degree of variability in severity. A prior study found that the CHD3 protein interacts with the protein encoded by FOXP2, a gene that has especially well-established links to speech development. Indeed, the speech capacities of individuals with de novo CHD3 mutations were more affected than would be expected based on general cognitive performance. Moreover, many patients had an unusually large head circumference, and characteristic facial features were seen in most of the individuals, giving clues to help recognize the disorder in clinical practice.

Mutations that disrupt gene function

In examining the nature of the mutations across the 35 different cases, the researchers noticed that many unrelated individuals had independent mutations clustering in one particular part of the gene, sometimes at exactly the same point of the DNA sequence. In collaboration with the research groups of Philippe Campeau (CHU Sainte-Justine, Montréal, Canada) and Paul Wade (NIEHS, USA), laboratory experiments were performed to test the impact of a selection of these mutations on the way CHD3 works. Most mutations clearly affected the capacity of CHD3 to regulate gene expression, but not all did so in the same manner.

Although CHD3 mutations are rare, it is hoped that publication of this article will allow identification of many additional individuals with this previously unrecognized disorder.  To understand more about the specific effects of CHD3 mutations, a follow-up research project is underway at the MPI’s Language & Genetics department, using cellular models and brain organoids to help decipher the roles of this gene in human brain development.  


Snijders Blok, L., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., et al. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9: 4619.

Funding note: This work was supported by the Language in Interaction consortium and the Max Planck Society.

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