Neurogenetics - Bruce LeFroy Centre

The Neurogenetics group was established in 2004 to develop laboratory-based molecular neuroscience research within the Murdoch Children's Research Institute (MCRI) and enhance the established clinical and public health research activities of the Bruce Lefroy Centre (BLC).

We work on gene discovery and functional characterisation of proteins contributing to neurodevelopmental and neurogenetic disorders including autism, brain malformations and ataxia.

Why genetic diagnosis matters

Identifying the genetic cause of a condition benefits both the individual and their family. A confirmed genetic diagnosis can:

• Improve clinical care and management
• Enable genetic counselling
• Support options such as pre-implantation genetic diagnosis
• Inform the development of targeted treatments or therapeutics

Our research focus

Our team is dedicated to improving the genetic and molecular basis of neurodevelopmental and neurogenetic disorders. Our research focuses on:

• Autism
• Brain malformations
• Epilepsy
• Ataxia

By combining gene discovery with functional studies, the research aims to uncover the molecular mechanisms that drive these conditions.

Cutting-edge technologies

Our team applies advanced genomic technologies to identify genetic changes that cause neurogenetic and neurodevelopmental disorders. These technologies include:

• High-density SNP arrays
• Next-generation sequencing, including both short-read and long-read

The characterisation of the disease-causing genes involves analysing cells and animal models to understand the molecular mechanism underlying the condition. Identification of disease-causing genes is beneficial to both the affected individual and their family.

Research goals

Our research aims to understand the mechanisms underlying disease and are an critical step toward developing treatment programs, as well as prevention or onset-delay strategies for brain and mind disorder.

Leadership and collaboration

The Centre is co-directed by Professor Martin Delatycki and Professor Paul Lockhart, both internationally recognised leaders in clinical genetics and molecular research.

Funding of BLC

The Bruce Lefroy Centre, made possible through the generosity of the Lefroy family and friends, recognises that families affected by rare neurodegenerative diseases cannot afford to wait.

Contact us

Professor Paul Lockhart, Group Leader / Co-Director BLC
Email:  show email address

Professor Martin Delatycki, Group Leader / Co-Director BLC
Email: [email protected]

Our projects

Towards treatment of intellectual disability caused by errors in the chromatin machinery

Intellectual disability affects approximately 2–3 per cent of newborns and can result from a range of causes, including environmental factors, chromosomal abnormalities, and single-gene variations.

Recently, it has been recognised that intellectual disability resulting from inborn errors in the chromatin machinery may be treatable. Over 70 genetic syndromes have been linked to disruptions in chromatin regulation.

This project focuses on neurodevelopmental conditions caused by variations in chromatin factors, because chromatin changes are reversible, and are therefore potential therapeutic targets.

More about this project

Using monogenic conditions to understand the neurobiology of autism

In approximately 15 to 20 per cent of individuals with autism, the condition is part of a clinically defined syndrome caused by a single gene disorder. Studying these studying these conditions provides a pathway to systematically explore the neurobiological mechanisms of Autism.

One such example is Neurofibromatosis type 1 (NF1)—an autosomal dominant disorder caused by a loss-of-function mutation in the NF1 gene.

This project investigates the developmental pathways to autism by combining:

• Accurate clinical phenotyping
• Neuronal modelling using patient-derived stem cells
• Laboratory-based assays to assess how brain cells grow, develop, and communicate

By identifying the dysregulated pathways in autism associated with NF1, this research offers valuable insights into the molecular mechanisms of autism. The findings have the potential to inform biomarker discovery, guide therapeutic development, and contribute to more targeted treatment strategies for Autism more broadly.

Discovery of new treatments for brain development disorders linked to epigenetic regulatory genes

Humans have a highly expanded cortex compared to other mammals which is responsible for our unique intellectual capacity.

During embryonic development, precise control of gene expression is essential to ensure that brain cells proliferate, differentiate, and mature at the right time.

This gene expression is largely governed by epigenetic markers on chromatin and DNA surrounding genes. It is therefore not surprising that mutations in epigenetic regulatory genes are frequently associated with cortical malformations and intellectual disability (ID).

This project uses a multi-systems approach to determine how mutations in chromatin regulator genes in individuals with intellectual disabilities affect cortical development. We use both:

• Patient-derived induced pluripotent stem (iPS) cells
• Mouse models

Because epigenetic modifications are reversible, we hypothesise that stimulating opposing epigenetic pathways may help restore balance. Our goal is to identify compounds that modulate histone methylation and acetylation pathways, to restore proper gene regulation during cortical development.

Understanding disease mechanism and improving clinical management of children with epilepsy

Epilepsy is a disorder of the brain that affects over 20 million children worldwide and is one of the medicine’s oldest recognised conditions. Children with epilepsy have recurrent seizures, which may present as staring spells, muscle jerks, loss of consciousness, or unusual sensations. Early diagnosis and intervention are critical to reduce seizure burden and prevent long-term developmental impacts.

While medications are the first line of treatment, they fail to provide seizure control in up to one-third of children and are often associated with side effects.

One of the most common causes of drug-resistant epilepsy in children is a brain lesion resulting from abnormal development during pregnancy. In these cases, surgical removal of the lesion can be curative.

In collaboration with the Epilepsy Surgery Unit at The Royal Children’s Hospital, our team is applying new molecular technologies to better understand the mechanisms of seizure generation. These include:

• Deep sequencing
• Single-cell omics
• 3D fluorescent imaging

By analysing brain tissue resected during surgery, we aim to uncover the molecular drivers of epilepsy and improve both surgical outcomes and clinical management for children living with this condition.

Understanding the molecular basis of CANVAS - a novel neurological disorder caused by an expanded DNA repeat

Repeat expansion disorders are a group of over 20 neurogenetic conditions that often present with overlapping and complex clinical symptoms. Collectively, they represent some of the most common genetic disorders encountered  by neurologists

Our team recently identified the genetic repeat expansion responsible for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Early findings suggest this may be the most common genetic cause of ataxia in humans.

Despite this discovery, little is known about the repeat size, structure, and variability of the CANVAS, or how these factors influence clinical presentation. This project aims to:

• Characterise the CANVAS repeat mutation using next-generation sequencing technologies
• Use patient-derived stem cells to model the effects of the repeat on nerve cells
• Investigate the molecular mechanisms driving disease progression

The insights gained will support genotype–phenotype correlations, improve clinical care, and help identify potential therapeutic targets for CANVAS and related disorders.

Determining the genetic basis of malformations of brain development

Malformations of brain development (MBDs) are relatively common and can lead to serious neurological conditions such as epilepsy, cerebral palsy, and developmental delay in children. Each year, more than 1,500 Australian children are born with an MBD, and tens of thousands of Australians are currently affected.

While genetic causes are believed to underlie the majority of MBDs, many of the responsible genes remain unidentified. A confirmed genetic diagnosis can:

• Improve prognosis and clinical care
• Enable accurate genetic counselling
• Support diagnostic and prenatal testing

Beyond diagnosis, studying individuals with MBDs enhances our understanding of brain development and function, and supports the advancement of genomic medicine and precision therapeutics.

This project uses advanced genomic technologies, including:

• Next-generation sequencing
• Single-cell omics approaches

Our goal is to identify the genes responsible for MBDs and understand the biological processes that disrupt normal brain formation during a child's development.

Funding

Thank you to our supporters.

• National Health and Medical Research Council
• Medical Research Futures Fund
• Royal Children’s Hospital Research Foundation
• The Orphan Disease Center (Million Dollar Bike Ride Grant Program)
• Stafford Fox Medical Research Foundation
• Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne

Collaborations

We partner with leading institutions worldwide, including:

• Professor Melanie Bahlo, Walter Eliza Hall Institute
• Professor Matthew Farrer, University of British Columbia
• Professor Linda Richards, Queensland Brain Institute
• Professor Stephen Robertson, University of Otago
• Professor Ingrid Scheffer, Melbourne Brain Centre
• IRC5 - International Research Consortium for the Corpus Collosum and Cerebral Connectivity

Featured publications

Rafehi H, Fearnley LG, Read J, Snell P, Davies KC, Scott L, Gillies G, Thompson GC, Field TA, Eldo A, Bodek S, Butler E, Chen L, Drago J, Goel H, Hackett A, Halmagyi GM, Hannaford A, Kotschet K, Kumar KR, Kumble S, Lee-Archer M, Malhotra A, Paine M, Poon M, Pope K, Reardon K, Ring S, Ronan A, Silsby M, Smyth R, Stutterd C, Wallis M, Waterston J, Wellings T, West K, Wools C, Wu KHC, Szmulewicz DJ, Delatycki MB, Bahlo M, Lockhart PJ. A prospective trial comparing programmable targeted long-read sequencing and short-read genome sequencing for genetic diagnosis of cerebellar ataxia, 2025, Genome Res. 2025 Apr 14;35(4):769-785.

S Donoghue, J Wright, AK Voss, PJ Lockhart, DJ Amor, The Mendelian disorders of chromatin machinery: Harnessing metabolic pathways and therapies for treatment, 2024, Molecular genetics and metabolism 142 (1), 108360

Kooshavar D, Amor DJ, Boggs K, Baker N, Barnett C, de Silva MG, Edwards S, Fahey MC, Marum JE, Snell P, Bozaoglu K, Pope K, Mohammad SS, Riney K, Sachdev R, Scheffer IE, Schenscher S, Silberstein J, Smith N, Tom M, Ware TL, Lockhart PJ, Leventer RJ. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations 2024, Brain communications.

Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14 2023, American Journal of Human Genetics, 2023 Jan 5;110(1):105-119.

K Davies, DJ Szmulewicz, LA Corben, M Delatycki, PJ Lockhart, RFC1-Related Disease: Molecular and Clinical Insights 2022, Neurology: Genetics 8 (5), e200016

Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, Davies KC, Lino-Coulon P, Colace C, Rafehi H, et al. (2022). Heterozygous PNPT1 variants cause spinocerebellar ataxia type 25. Annals of Neurology, 92(1), 122–137.

Stephenson SEM, Costain G, Blok LER, Silk MA, Nguyen TB, Dong X, Alhuzaimi DE, Dowling JJ, Walker S, Amburgey K, Hayeems RZ, Rodan LH, Schwartz MA, Picker J, Lynch SA, Gupta A, Rasmussen KJ, Schimmenti LA, Klee EW, Niu Z, Agre KE, Chilton I, et al. (2022). Germline variants in tumour suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. American Journal of Human Genetics, 109(4), 601–617. 

Lockhart PJ. Advancing the diagnosis of repeat expansion disorders. Lancet Neurol. 2022 Mar;21(3):205-207. doi: 10.1016/S1474-4422(22)00033-3. PMID: 35182498.

Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, Gillies G, Diakumis P, Dolzhenko E, Eberle MA, García Barcina M, Breen DP, Chancellor AM, Cremer PD, Delatycki MB, Fogel BL, Hackett A, Halmagyi GM, Kapetanovic S, Lang A, Mossman S, Mu W, Patrikios P, Perlman SL, Rosemergy I, Storey E, Watson SRD, Wilson MA, Zee DS, Valle D, Amor DJ, Bahlo M, Lockhart PJ. (2019). Bioinformatics-based identification of expanded repeats: A non-reference intronic pentamer expansion in RFC1 causes CANVAS. American Journal of Human Genetics, 105(1), 151–165. 

Marsh AP, Heron D, Edwards TJ, Quartier A, Galea C, Nava C, Rastetter A, Moutard ML, Anderson V, Bitoun P, Bunt J, Faudet A, Garel C, Gillies G, Gobius I, Guegan J, Heide S, Keren B, Lesne F, Lukic V, Mandelstam SA, McGillivray G, McIlroy A, Méneret A, Mignot C, Morcom LR, Odent S, Paolino A, Pope K, Riant F, Robinson GA, Spencer-Smith M, Srour M, Stephenson SE, Tankard R, Trouillard O, Welniarz Q, Wood A, Brice A, Rouleau G, Attié-Bitach T, Delatycki MB, Mandel JL, Amor DJ, Roze E, Piton A, Bahlo M, Billette de Villemeur T, Sherr EH, Leventer RJ, Richards LJ, Lockhart PJ, Depienne C. (2017). Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nature Genetics, 49(4), 511–514.