PhD Project 23

Genomics of speech and language disorders: the next generation

 

PhD-candidate: Lot Snijders-Blok
PIs: Han Brunner (WP6) and Simon Fisher (WP5)
Start date: 15 February 2016

(last update 2019-07-01)

Research Content

After 15 years of intensive research, FOXP2 is the only well-characterized gene implicated in speech and language disorder. Other candidates have started to emerge, but often the definitions of phenotypes associated with gene disruption are incomplete, especially with regard to speech and language profiles. Moreover, the crucial molecular mechanisms remain elusive. Studies of neuro-developmental disorders like intellectual disability have been transformed by advances in genomics, with state-of-the-art mutation screens yielding major new insights. Such advances have not yet been applied in the language sciences. The current project addresses this gap, uniting in-depth phenotyping, whole genome sequencing, analyses of molecular networks and neuroimaging genetics, to shed new light on neurobiological bases of speech and language.

Highlight

The identification of a new cause of developmental disorders that include severe speech/language problems
Team members: Snijders Blok, Fisher, Brunner, and many other (inter)national researchers

This research project started with the finding of a highly interesting mutation in the CHD3 gene in a child with a severe speech disorder. The aim of this project was to find out if mutations in CHD3 could be the cause of this neurodevelopmental disorder, and to characterize the clinical and molecular spectrum of this new disorder.
By using an international network of clinicians and researchers, a total of 35 unrelated individuals was identified, all carrying de novo mutations in CHD3. The range of clinical features of this newly discovered data was defined, and it turned out that all patients had developmental delays with often severely affected speech capacities and a large head circumference. In collaboration with other research groups in Canada and the USA, laboratory experiments were performed to test the impact of the mutations. Most mutations clearly affected the capacity of the CHD3 protein to regulate gene expression. 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.

This research project is a perfect example of interdisciplinary research, as clinical and molecular researchers from many different backgrounds and with different areas of expertise on molecular pathways and laboratory techniques were involved.
This CHD3-associated disorder could only have been identified by international collaboration and team science. Many children with monogenic causes of speech/language disorders have a rare genetic cause that can only be better understood by extensive collaboration.

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Progress 2018

Two studies have been published in 2018. One study shows that mutations in the MED13 gene can cause a neurodevelopmental disorder that includes severe speech and language disorders. The other study described a new neurodevelopmental disorder caused by mutations in the CHD3-gene, on a clinical and molecular level. This newly characterized disorder has recently been renamed as Snijders Blok-Campeau syndrome. A publication on a third gene is currently under review at a high quality journal.
The SATB2 study, in which speech/language phenotyping will be performed in individuals with SATB2-associated syndrome, received approval from the ethical committee by the end of 2018.
In addition to the results above, more clinical and molecular work is currently being performed on additional candidate genes. Also, a research proposal for a whole genome sequencing study in children with severe developmental language disorders is written to undergo review of the applicable ethical committee.

Groundbreaking characteristics

This project involves collaboration between two PIs with a different background and research focus. These two researchers have complementary expertise: Brunner is an expert on clinical syndromology of neurodevelopmental disorders, while Fisher's research focuses on the molecular basis of speech and speech impairments. In this project an innovative approach will be applied, combining deep (neurolinguistic) phenotyping with gene discovery, pathway analysis and neuroimaging genetics.