“Diagnostic odyssey” over for individuals with rare intellectual disability thanks to novel gene discovery

In a world-first, variants in the ZMYND8 gene have been linked to a novel neurodevelopmental syndrome.

An international collaboration of clinical and translational genomics researchers led by Associate Professor Tony Roscioli at Neuroscience Research Australia (NeuRA), UNSW Sydney and New South Wales Health Pathology’s Randwick Genomics Laboratory and Dr. Colleen Carlston at Boston Children’s Hospital and Harvard Medical School, has discovered 11 novel genetic variants in the gene ZMYND8 associated with a new neurodevelopmental disorder with intellectual disability and cardiac malformations.

Functional work with the laboratories of Professor Robert Harvey at the University of the Sunshine Coast, Professor Annette Schenck at Radboud University Medical Center and Associate Professor Irina Voineagu at UNSW Sydney also showed that ZMYND8 is developmentally regulated in the brain and that ZMYND8 variants abolish key interactions with neuronal proteins including histones, Drebrin and GATAD2A, and impair learning in Drosophila models.

The publication of this research today in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG) means Australian families with alterations in ZMYND8 can finally get a diagnosis and gain access to critical NDIS funding and support.

There are over 7,000 rare diseases in the population. For individuals living with a rare disease, it can be a challenging and isolating experience. Difficulties in obtaining an accurate diagnosis mean that individuals with rare disease often live with ongoing uncertainty in terms of how their disease will progress and are unable to access therapies and treatments that could dramatically improve their quality of life.

In this study, researchers identified an international cohort of individuals with intellectual disability and damaging alterations in the ZMYND8 gene. This gene was already known to have important functions in humans such as in DNA repair, transcription regulation and supressing tumours, but hadn’t previously been linked to human cognition and learning. Functional studies also revealed that ZMYND8 variants abolish binding to other proteins involved in synapse formation and responses to DNA damage.

The importance of this study is that ZMYND8 has been characterised as a novel intellectual disability gene,” said Kerith-Rae Dias, PhD candidate at NeuRA and UNSW Sydney and one of the lead authors of the paper.

The 11 families in this cohort now have a definitive genetic diagnosis. This allows them to access disability funding and build support via connections with other families with ZMYND8 alterations. It also means future families with ZMYND8 variants can access a rapid diagnosis after genetic testing and avoid a lengthy journey that can include unnecessary referrals to several specialists, invasive tests, misdiagnosis and years of financial and social costs.”

Intellectual disability is significantly driven by de novo variants, which arise in the child rather than being inherited from the parents.

The variants found in ZMYND8 are all de novo and this is important because it is unlikely that the family would have another affected child should they decide to have more children.”

Our cohort also gives us clues as to how these particular ZMYND8 variants might be disrupting early brain development and contributing to intellectual disability,” says Kerith-Rae. However, more cases will help further delineate this novel syndrome and provide more insights into the underlying biological mechanisms.”

A/​Prof Tony Roscioli, Neurogenomics Group lead at NeuRA and UNSW Medicine & Health, and clinical geneticist at Sydney Children’s Hospital, said of the research:

This work shows the importance of resourcing genomic testing for families to make diagnoses for them. A single gene can have multiple functions depending on how it interacts with other genes. It will be important to continue this work as ZMYND8 links to many proteins important for human cognition.”

The study was largely funded through the Australian National Health and Medical Council’s (NHMRC) support of the Centre for Excellence in Neurocognitive Disorders.

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About Neuroscience Research Australia (NeuRA)
Neuroscience Research Australia (NeuRA) is an independent, not-for-profit research institute based in Sydney aiming to prevent, treat and cure brain and nervous system diseases, disorders and injuries through medical research.

To learn more about NeuRA: https://​www​.neu​ra​.edu​.au/

2 August 2022

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