Translational Neurogenetics Laboratory

Research Overview

The focus of the Translational Neurogenetics Laboratory is to understand the basic neurobiology of epilepsy, speech disorders and vascular malformations, and translate this knowledge into improved treatment of patients. This group is part of the Epilepsy Research Centre at the Austin Hospital academic node.

Hidden Genetics of Epilepsy: Somatic Mutations in Surgical Tissue

Somatic mutagenesis, occurring post-fertilization, may play an important role in causation of the severe end of the focal epilepsy spectrum. To unravel this contribution, we are studying two privileged resources. First, a unique set of > 100 patients with focal epilepsy refractory to anti-seizure medications (ASMs) who have had epilepsy surgery and have fresh frozen brain tissue available for genetic analysis. Second, our biobank of > 200 formalin-fixed paraffin-embedded (FFPE) brain specimens resected from patients with focal epilepsy over the last 10 years. We are applying molecular inversion probe (MIP) gene capture panel, exome and RNA sequencing, respectively, which are well established techniques for deep sequencing brain tissue in our hands.

Genetics of Speech and Language Disorders

Revealing the genetic causes of speech and language disorders helps us to understand the underlying neurobiology. We have identified 33 genes that cause severe childhood speech disorder based on detailed phenotypic analysis. We have shown that gene discovery coupled with cutting-edge imaging can elucidate neural pathways involved in speech disorders. Together, our genetic and MRI studies have produced the most definitive, empirically-based, model of human speech production and have led to changes in treatment for individuals with this genetic disease.

Molecular Diagnosis of Vascular Malformations for Clinical Trials

We sequence lesional DNA from children and adults with vascular malformations to confirm the presence of a targetable somatic mutation and administer a twelve month trial of either the PI3K inhibitor alpelisib or MEK inhibitor trametinib appropriate to the identified mutation. Effectiveness is assessed using a novel, personalised outcome measurement strategy. This is the first prospective clinical trial in vascular malformations in Australia, and thus the first opportunity for these patients to benefit from participating in a clinical trial.  A successful outcome will translate immediately into clinical care for study patients and for others with vascular malformations in Australia and around the world.

Genetic Susceptibility to Febrile Seizures

Febrile seizures (FS) are the most common seizure syndrome that can lead to epilepsy later in life.  Mutations in the sodium channel subunit gene SCN1A can give rise to FS but also to epilepsies such as Dravet syndrome. Current evidence suggests genetic factors play an important role in determining FS susceptibility. We have identified ion channel and transporters, and synaptic protein genes that confer susceptibility to FS. Our laboratory has a strong interest in discovering and characterising other FS susceptibility genes.

Staff

    Laboratory Head
  • Associate Professor Michael Hildebrand, Principal Research Fellow, Epilepsy Research Centre, Department of Medicine, Melbourne Medical School, Austin Health; Honorary, Neurosciences Group, Murdoch Children’s Research Institute (https://findanexpert.unimelb.edu.au/profile/5791-michael-hildebrand)
  • Senior Scientists
  • Dr Mark Bennett, Senior Research Fellow (https://findanexpert.unimelb.edu.au/profile/178792-mark-bennett)
  • Research Associates

  • Neblina Sitka, Bioinformatics
  • PhD Students
  • Tim Green
  • Zimeng Ye
  • Masters Students
  • Joshua Reid
  • Medical Students
  • Kevin Mao
  • Senior Research Assistants
  • Tom Witkowski
  • Research Assistants
  • Joshua Reid
  • Tim Green
  • Technical Assistants
  • Harshini Thiyagarajah
  • Clinical Affiliates
  • Professor Samuel Berkovic (https://findanexpert.unimelb.edu.au/profile/16510-sam-berkovic)
  • Professor Ingrid Scheffer (https://findanexpert.unimelb.edu.au/profile/15260-ingrid-scheffer)
  • Professor Angela Morgan (https://findanexpert.unimelb.edu.au/profile/200994-angela-morgan)
  • Professor Tony Penington (https://findanexpert.unimelb.edu.au/profile/13501-anthony-penington)
  • Professor David Amor (https://findanexpert.unimelb.edu.au/profile/17953-david-amor)
  • Associate Professor Piero Perucca (https://findanexpert.unimelb.edu.au/profile/815937-piero-perucca)
  • Dr Natasha Brown (https://findanexpert.unimelb.edu.au/profile/827469-natasha-brown)
  • Discovery Affiliates
  • Professor Melanie Bahlo (https://findanexpert.unimelb.edu.au/profile/20936-melanie-bahlo)
  • Professor Steve Petrou (https://findanexpert.unimelb.edu.au/profile/2578-steven-petrou)
  • Professor Christopher Reid (https://findanexpert.unimelb.edu.au/profile/17917-christopher-reid)

Collaborators

  • Professor Samuel Berkovic, Epilepsy Research Centre, University of Melbourne
  • Professor Ingrid Scheffer, Epilepsy Research Centre, University of Melbourne
  • Associate Professor Angela Morgan, Murdoch Children's Research Institute
  • Professor Melanie Bahlo, Walter and Eliza Hall Institute
  • Professor Patrick Kwan, Royal Melbourne Hospital
  • Associate Professor Heather Mefford, University of Washington

Funding

  • Using Cerebrospinal Fluid Liquid Biopsy for Detection of Mosaic Brain Mutations
    Hildebrand MS, Poduri A, Perucca P
    CIA NHMRC Ideas Grant APP2012287
    2022
    3 years; $909,173 AUD
  • Translational Centre for Speech Disorders
    Morgan AT, Scheffer IE, Reilly S, Hildebrand MS, Amor D, Best S, Vogel A, Coman D, Fisher S, Liegeois F
    CID NHMRC CRE Grant APP2015727
    2022
    5 years; $2,500,000 AUD
  • PERSYST: Pathogenic Evaluation of Recalcitrant Variants by Systematic Transactivation
    Gecz J, Jolly L, van Eyk C, Pflueger C, Voineagu I, Hildebrand MS, Scheffer IE, Poulton C, Berkovic SF, Barry S, Tan TY, Coman D, Lister R, Barnett C, Baynam G
    CIF MRFF GHFM1 Grant APP2016447
    2022
    5 years; $2,996,428 AUD
  • “Integrative-omics” for Precision Medicine in the Epilepsies
    Scheffer IE, Gecz J, Halgamuge S, O’Brien TJ, Petrou S, Berkovic SF; AIs Perucca P, Howell K, Hildebrand MS, Palmer E, Sadikovic B
    AI NHMRC Synergy Grant APP2010562
    2022
    5 years; $5,000,000 AUD
  • Centre for Research Excellence in Developmental and Epileptic Encephalopathies
    Scheffer IE, Howell K, Palmer E, Wakefield C, Lah S, Hildebrand MS, Dalziel K, Petrou S
    CIF NHMRC CRE Grant APP2006841
    2021
    5 years; $2,500,000 AUD
  • Precision Diagnosis for the Remaining 50% of Unsolved Developmental and Epileptic Encephalopathies
    Hildebrand MS, Scheffer IE, Perucca P, Berkovic SF, Howell K, Bennett MF
    CIA MRFF GHFM1 Grant APP2007707
    2021
    5 years; $2,992,144.21 AUD
  • Targeted Therapies for Vascular Malformations
    Penington A, Luen S, Hildebrand MS, Desai J, Rosenthal M, Brown N, Hansford J CIC MRFF RCRDUN Clinical Trial Grant  APP2006631
    2021
    5 years; $1,699,253.60 AUD
  • Discovering genes for singing ability in Australian families
    Wilson S, Berkovic SF, McPherson G, Peretz I; AI: Hildebrand MS
    AI ARC Discovery Project DP200100961
    2020
    4 years; $539,000 AUD
  • A Clinical Liquid Biopsy to Diagnose Epilepsy
    Hildebrand MS, Berkovic SF, Bahlo M, Scheffer IE, Leventer R
    CIA Australian Epilepsy Foundation Research Fund Grant
    2020
    4 years; $224,640 AUD

Research Publications

    Selected recent publications (total of 136 publications @ 26/10/22):

    • Ye Z, Bennett MF, …Scheffer IE, Berkovic SF, Perucca P, Hildebrand MS*. Somatic mosaic mutation gradient detected in trace brain tissue from stereo-EEG depth electrodes. Neurology. Accepted 9th Sep (2022)
    • Kaspi A, Hildebrand MS, … Amor DJ, Scheffer IE, Bahlo M, Morgan AT. Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development. Mol Psychiatry. Sep 18. doi: 10.1038/s41380-022-01764-8. Epub ahead of print (2022)
    • Ye Z, Lin S, Zhao X, Bennett MF, … Berkovic SF, Scheffer IE, Liao J, Hildebrand MS*. Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting. Hum Mutat. Aug 28. doi: 10.1002/humu.24454. Epub ahead of print (2022)
    • Gozzelino L, … Scheffer IE, Bahlo M, Berkovic SF, Hildebrand MS, …Pippucci T. Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy. Brain. 2022 Jul 29;145(7):2313-2331.
    • Green TE, Motelow JE, Bennett MF, Ye Z, … Scheffer IE, … Berkovic SF, Hildebrand MS*. Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions. Hum Mol Genet. 2022 Jul 21;31(14):2307-2316.
    • Stephenson SEM, …Amor DJ, Boyce JO, Morgan AT, Hildebrand MS, … Tan TY. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. Am J Hum Genet. Apr 7;109(4):601-617 (2022)
    • Rouxel F, Relator R, …Hildebrand MS, …Morgan AT, … Sadikovic B, Genevieve D. CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature. Genet Med. May;24(5):1096-1107 (2022)
    • Yeom D, … Hildebrand MS, Berkovic SF, McPherson GE, Peretz I, Wilson SJ. Genetic factors and shared environment contribute equally to objective singing ability. iScience. 2022 May 6;25(6):104360 (2022)
    • Thompson-Lake DGY, … Bahlo M, Scheffer IE, Hildebrand MS, Liégeois FJ, Morgan AT. Atypical development of Broca's area in a large family with inherited stuttering. Brain. 145(3):1177-1188 (2022)
    • Green TE, Scheffer IE, Berkovic SF, Hildebrand MS*. UNC13B and focal epilepsy. Brain. Apr 29;145(3):e10-e12 (2022)
    • Bennett MF*, Hildebrand MS*, … Gécz J, Bahlo M, Scheffer IE, Berkovic SF. Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy. Neurol Genet. Jan 25;8(1):e652 (2022)
    • Green TE, … Bennett MF, Hildebrand MS*, Berkovic SF*. Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome. Eur J Hum Genet. Mar;30(3):384-388 (2022)
    • Skotte L, … Hildebrand MS, … Scheffer IE, … Berkovic SF, Werge T, Feenstra B. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes. Brain. Apr 18;145(2):555-568. (2022)

Research Projects




Key Contact

For further information about this research, please contact Associate Professor Michael Hildebrand, PhD

Department / Centre

Medicine

Unit / Centre

Translational Neurogenetics Laboratory

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