You are here

Genetics and development

Program leader: Jonathan Payne

Overview

The vision of the Genetics and Neurodevelopment team is to better understand the developmental neuroscience and abnormal psychology of genetic conditions that cause common neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Rather than researching these neurodevelopmental disorders in the general population, in which the cause of the condition is unknown, our research examines the mechanisms underlying neurodevelopmental pathology in the context of a single gene mutation where the cause is known. 

Our research program integrates four main goals: (1) characterising symptoms and clinical outcomes (2) identifying novel neuroimaging markers (3) disease modelling using state-of-the-art laboratory protocols and (4) translating findings into disease-directed clinical trials. 

Characterising the neurodevelopmental profile of children with a single gene mutation will further our understanding of the difficulties and outcomes experienced as part of these conditions. Our research will have significant implications for developing novel disease modelling and drug screening methods to help identify new treatment pathways and to stratify patients for clinical trials. This approach is expected to lead to improved treatment efficacy and more personalised treatment approaches for individuals with these genetic conditions.

Projects

  1. A multimodal study of social functioning and autism spectrum disorder in children with neurofibromatosis type 1 (NF1)

In the general population, autism spectrum disorder (ASD) is a complex polygenic disorder in which children experience significant impairments in social interaction, communication, and restricted interests and behaviours. The cause of ASD remains poorly understood, and because of this, we are unable to reliably identify atypical brain pathways that may contribute to the disorder, and thus, ways to treat problem. This study investigates ASD in children that have a mutation within their NF1 gene. Because we know the cause, this study will shed light onto one potential pathway to autism, that caused by NF1. 

This is a cross sectional study involving 200 children with NF1, typically developing children and also children with ASD from the general population. All participants complete extensive clinical phenotyping and those that screen at risk for ASD will complete a detail assessment for ASD. Participants will undergo structural and functional brain scans to determine whether there are identifying markers that can be used to distinguish children with autism. To examine early markers of ASD, younger participants will complete a novel eye-tracking paradigm which assesses eye-gaze patterns in relation to social stimuli and shapes. We are also collecting blood from consenting participants to model neurodevelopmental disorders in the laboratory and examining proof-of-principle drug screening. 

  1. Social functioning and autism spectrum disorder in children and adolescents with Noonan syndrome

Noonan syndrome (NS) is a relatively common genetic syndrome with variable features including short stature, congenital heart disease, distinctive facial characteristics, skeletal anomalies, and varying degrees of developmental delay. Research in the past decade suggests that individuals with NS may experience a range of cognitive, behavioural and social difficulties, including symptoms of autism spectrum disorder (ASD). Despite some preliminary research in this area, outcomes in individuals with NS are highly variable and we currently know very little about the nature and causes of the cognitive, social and behavioural difficulties experienced by children and adolescents living with NS. 

This cross-sectional pilot study will involve 70 children and adolescents with NS who will all complete detailed assessment of cognition, language, memory, attention, visual perception, adaptive behaviour, social skills, and mental health concerns. Individuals who screen at risk for ASD complete detailed assessments for ASD. In addition, participants will complete MRI brain scans, which will allow us to examine whether cognitive and behavioural outcomes across individuals with NS relate to differences in brain development and function. We will also assess whether variability in outcomes depends on the particular gene where a mutation is found, as well as factors related to medical severity and the family environment. This study will generate important new knowledge regarding the nature and causes of difficulties experienced by children and adolescents with NS, and inform optimal design of educational and therapeutic interventions. 

  1. Quantification of GABA in children with neurofibromatosis type 1 using magnetic resonance spectroscopy: a cognitive biomarker?

In this study we are using a brain imaging technique magnetic resonance spectroscopy (MRS) to examine the brain neurotransmitter GABA in children with NF1 in comparison to typically developing children. We aim to determine whether GABA levels are abnormal in particular brain regions of children with NF1, and if so, determine whether these abnormal GABA levels are indicators of the cognitive difficulties experienced by some children with NF1.

  1. Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1

This is a registered (ACTRN12619000525189), randomised controlled trial investigating whether methylphenidate is effective in treating cognitive deficits and attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1. It is a cross-over study, meaning that study participants complete 6 weeks of methylphenidate treatment followed by 6 weeks of placebo or vice versa. Both participants and investigators are blinded to the treatment sequence. This study is a collaboration with the Kids Neuroscience Centre in Sydney (The Children’s Hospital at Westmead).

  1. Trametinib in neurofibromatosis-associated tumours (TiNT)

This is an open label, multisite phase II study of trametinib in paediatric, adolescent and young adults with NF1-associated tumours (plexiform neurofibromas, optic pathway gliomas) conducted across sites in Australia and New Zealand. Trametinib is a medication from the MEK inhibitor family, which can be used to downregulate the RAS/MAPK pathway, which is overactive in NF1. Tumour responses will be measured over the two year treatment period radiologically and functionally by visual assessments and/or quality of life and pain scores. Because this pathway is also thought to be critical to healthy neurodevelopment, cognitive and behavioural outcomes at baseline 6, 12 and 24 months will also be measured and compared to a comparison group consisting of untreated patients with NF1 with a similar age distribution. 

  1. Intervention trial for cognitive deficits in neurofibromatosis type 1: efficacy of computerised cognitive training

This Phase II randomized parallel group controlled trial compares the efficacy of two interventions on cognitive outcomes in children with NF1 (r. Participants are randomized to either the active treatment, called Cogmed, or the active control condition which is a computerised program targeting academic skills (e.g., reading comprehension). Cogmed is a computerised gamified working memory training program targeting the ability to ‘hold’ and ‘mentally manipulate’ information in mind, such as performing mental arithmetic. Working memory is important for the development of academic skills, such as reading and maths, where children are required to hold and work with multiple units of information in their minds. This study is an international collaboration between, the Children’s National Health System, Boston Children’s Hospital, Children’s Hospital Los Angeles, The Children’s Hospital at Westmead, and MCRI (ClinicalTrials.gov Identifier: NCT02944032).

  1. Pilot intervention trial for assistive listening devices in children with NF1 and auditory processing deficits. 

This is a registered (ACTRN12619000525189) Phase I randomised, blinded, two period crossover pilot study of 10 participants, investigating the use of remote microphone assistive listening devices in treating auditory processing deficits in NF1. The devices are non-invasive wireless sound transmission devices that optimise the listening environment by improving signal-to-noise ratios. Although these devices have never been trialled before in children with NF1, emerging evidence from the general population suggests they are practical for children to use and result in improved speech perception, academic performances (e.g., reading) and interpersonal relationships, in children with auditory processing deficits. 

Selected Publications

  1. Payne JM, Barton B, Ullrich NJ, Cantor A, Hearps SJC, Cutter G, Rosser T, Walsh KS, Gioia GA, Wolters PL, Tonsgard J, Schorry E, Viskochil D, Klesse L, Fisher M, Gutmann DH, Silva AJ, Hunter SJ, Rey-Casserly C, Cantor NL, Byars AW, Stavinoha PL, Ackerson JD, Armstrong CL, Isenberg J, O’Neil SH, Packer RJ, Korf B, Acosta MT, North KN (2016). A randomized placebo-controlled study of lovastatin in children with neurofibromatosis type Neurology, 87:1-10.
  2. Payne JM, Porter MA, Pride NA, North KN (2016). Theory of mind in children with neurofibromatosis type 1. Neuropsychology, 16:439-48.
  3. Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN (2016). Disease burden and symptom structure of autism in neurofibromatosis type 1: a study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry, 73:1276-84.
  4. Pride NA, Korgaonkar M, North KN, Barton B, Payne JM (2017). The neural basis of deficient response inhibition in children with neurofibromatosis type 1: evidence from a functional MRI study. Cortex, 93:1-11.
  5. Lewis AK, Porter MA, Williams TA, Bzishvili S, North KN, Payne JM (2017). Facial emotion recognition, face scan paths, and face perception in children with neurofibromatosis type 1. Neuropsychology, 31:361-70.
  6. Chisholm AK, Anderson VA, Pride NA, North KN, Payne JM (2018). Social function and autism spectrum disorder in children with neurofibromatosis type 1: a systematic review. Neuropsychology Review, 28:317-40.
  7. Pride NA, Korgaonkar M, North KN, Payne JM (2018). Impaired engagement of the ventral attention system in neurofibromatosis type 1. Brain Imaging and Behavior, 12:499-508.
  8. Lewis AK, Porter MA, Williams TA, Bzishvili S, North KN, Payne JM (2019). Reduced attention to faces in children with neurofibromatosis type 1: eye-tracking within a social context. Developmental Medicine & Child Neurology, 61:174-80
  9. Haebich KM, Pride NA, Walsh KS, Chisholm A, Rouel M, Maier A, Anderson V, Barton B, Silk T, Korgaonkar MS, Seal M, Lami F, Lorenzo J, Williams K, Dabscheck G, Rae CD, Kean M, North KN, Payne JM (2019). Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study. BMJ Open http://dx.doi.org/10.1136/bmjopen-2019-030601.
  10. Payne JM, Hearps SJC, Walsh KS, Paltin I, Barton B, Ullrich NJ, Haebich, KM, Coghill D, Cantor A, Cutter G, Tonsgard JH, Viskochil D, Rey-Casserly C, Schorry EK, Ackerson JD, Klesse L, Fisher MJ, Gutmann DH, Rosser T, Packer RJ, Korf B, Acosta MT, North KN for the NF Clinical Trials Consortium (in press). Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1. Annals of Clinical and Translational Neurology.
  11. Payne JM, Haebich KM, MacKenzie R, Walsh KS, Hearps SJC, Coghill D, Barton B, Pride NA, Ullrich NJ, Tonsgard JH, Viskochil D, Schorry EK, Klesse L, Fisher MJ, Gutmann DH, Rosser T, Packer RJ, Korf B, Acosta MT, Bellgrove M, North KN for the NF Clinical Trials Consortium (in press). Cognition, attention deficit hyperactivity disorder and functional impairment in children and adolescents with neurofibromatosis type 1. Journal of Attention Disorders.

Funding

Our research is supported by funding from the US Department of Defense Neurofibromatosis Research Program, the Children’s Tumor Foundation (US), the Children’s Tumour Foundation (Australia), National Health and Medical Research Council, Flicker of Hope and the Murdoch Children’s Research Institute. Dr Payne holds a MCRI Clinician Scientist Fellowship. 

Positions available

We are currently recruiting high quality students with a background in psychology or neuroscience who wish to undertake post-graduate or honours-level research into genetics and neurodevelopmental disorders. Interested applicants should email Dr Jonathan Payne at: jonathan.payne@mcri.edu.au

Team

  • Dr Jonathan Payne, Senior Research Fellow
  • Dr Kristina Haebich, Research Officer
  • Dr Nicholas Ryan, Research Officer
  • Ms Alice Maier, Research Psychologist
  • Dr Hayley Darke, Research Psychologist
  • Ms Francesca Lami, Research Psychologist
  • Ms Anita Chisholm, PhD student
  • Dr Lauren Taylor, Masters student
  • Ms Rebecca Dilworth, Masters student
  • Ms Rachel MacKenzie, Masters student
  • Ms Emma Giliberto, Masters student
  • Ms Tracey Chau, Honours student
  • Ms Zamantha Munoz Rodriguez, International Masters student
  • Ms Kylie Clarke, Clinic Support Co-ordinator
  • Ms Marquelle Goods, Volunteer
  • Ms Jashmina Shetty, Volunteer 
  • Mr Duy Dao, Volunteer
  • Ms Natasha Hogan, Volunteer
  • Ms Nicole Doyle, Volunteer