Global study identifies new intellectual disability and its genetic cause

A global research collaboration has revealed a hidden cause of a rare intellectual disorder associated with severe language delay, epileptic seizures, motor impairment and brain abnormalities. The study, led by the University of the Sunshine Coast, Radboudumc, Neuroscience Research Australia and the University of Zürich, was published in Genetics in Medicine.

The researchers describe a new form of childhood genetic intellectual disability resulting from recessive variants in the gene GTF3C3. UniSC professor in pathophysiology Robert Harvey said the findings may lead to a faster diagnosis and support for children with neurodevelopmental disorders and their families: “It is important for families to understand the genetic basis of these disorders, due to the frequency and risk of recurrence of autosomal recessive forms of intellectual disability.  Importantly, we revealed a hidden mechanism of the disease. This could have implications for other neurodevelopmental disorders, such as autism spectrum disorder, cerebral palsy, dyslexia, seizures and attention deficit hyperactivity disorder.”

Disturbing mutations

The team of researchers investigated data from 12 individuals from seven families with rare GTF3C3 variants, who had been referred from institutions in Australia, Egypt, Germany, Saudi Arabia, Switzerland, the Netherlands, the United Kingdom, and the USA. While the GTF3C3 gene has previously been implicated in isolated cases of neurodevelopmental disorders, the study firmly established that the majority of GTF3C3 mutations led to a loss of function.

Animal models of the novel disorder

The team of researchers at Radboudumc in the Netherlands also genetically engineered an animal model, the fruit fly Drosophila, to induce loss of function of GTF3C3. “Flies with reduced levels of GTF3C3 show increased seizure-like behaviour, motor impairment and deficits in learning, recapitulating several clinical features of the disorder”, explains Prof. Annette Schenck. “This provided independent support that mutations in GTF3C3 are causally underlying the disorder. While many other research groups perform such analyses in mouse models, flies are much more time and costs efficient, and raise no ethical concerns. This allows us to minimize the time until patients can benefit from the findings of the whole project team”.

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Paper in Genetics in Medicine: Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability – Lachlan De Hayr, Laura E.R. Blok, Kerith-Rae Dias, Jingyi Long, Anaïs Begemann, Robyn D. Moir, Ian M. Willis, Martina Mocera, Gabriele Siegel, Katharina Steindl, Carey-Anne Evans, Ying Zhu, Futao Zhang, Michael Field, Alan Ma, Lesley Adès, Sarah Josephi-Taylor, Rolph Pfundt, Maha S. Zaki, Hoda Tomoum, Anne Gregor, Julia Laube, André Reis, Sateesh Maddirevula, Mais O. Hashem, Markus Zweier, Fowzan S. Alkuraya, Reza Maroofian, Michael F. Buckley, Joseph G. Gleeson, Christiane Zweier, Mireia Coll-Tané, David A. Koolen, Anita Rauch, Tony Roscioli, Annette Schenck, Robert J. Harvey

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