Catalyst grant awardees
Stream 1 funding supports projects that aim to resolve the genetic diagnosis of a single patient with variant/s of uncertain significance in a known or novel disease gene.
The AFGN has awarded a total of $675K to stream 1 projects to date (August 2023).
Novel gene | Prof Natasha Harvey, UniSA
The AFGN awarded $30,000 to Prof Natasha Harvey at the University of South Australia in July 2022 to develop a mouse model to establish a novel gene disease association with neural, cardiac and lymphatic vascular defects.
Novel gene | Prof Sally Dunwoodie, VCCRI
In July 2022, $30,000 was awarded to Prof Sally Dunwoodie at the Victor Chang Cardiac Research Institute to develop a mouse model to establish a novel gene disease association for congenital heart defects.
Novel gene | Robert Bryson-Richardson & Diane Fatkin, Monash & VCCRI
Prof Robert Bryson-Richardson at Monash Unviersity and Prof Diane Fatkin at the Victor Chang Cardiac Research Insitute were awarded $45,000 in July 2022 to study a novel gene disease associated with perinatal lethal cardiomyopathy using Zebrafish.
In July 2022, Prof Sally Dunwoodie from the Victor Chang Cardiac Research Institute was awarded $45,000 to create a mouse model to establish a novel gene disease association with congenital heart defects.
Novel gene | Prof Nathan Palpant, UQ
With $45,000 in funding awarded in July 2022, Prof Nathan Palpant at the University of Queensland will employ iPSC modelling techniques to establish a novel gene disease association for a patient with congenital heart defects.
Novel gene | Dr Chris Hahn, SA Pathology
In July 2022, Dr Chris Hahn at SA Pathology was awarded $30,000 will create a mouse model to establish a novel gene disease association in a family with cytopenia’s and haematopoietic malignancy.
CAV3 | Prof Robert Parton, UQ
Prof Robert Parton at the University of Queensland was awarded $60,000 in October 2022 to investigate variants in CAV3 associated with skeletal myopathy using Zebrafish.
TERT | Prof Tracy Bryan, CMRI
In October 2022, Prof Tracy Bryan at the Children’s Medical Research Institute was awarded $60,000 to functionally validate VUS from two patients with telomere biology disorder using a molecular dynamics modelling and an in vitro telomerase activity assay.
STAG2 | Prof Mathew Jones, UQ & Prof Gary Hime, UoM
In November 2022, two complementary projects were individually funded to study a VUS from a family who had a stillborn child with multiple congenital anomalies. Prof Mathew Jones at the University of Queensland will perform analysis using a cellular assay while Prof Gary Hime at the University of Melbourne will study the variants in fruit fly. Both researchers were awarded $30,000 to support their work.
FBXL4 | Dr Julia Pagan, UQ
Dr Julia Pagan, at the University of Queensland was awarded $45,000 in March 2023 to functionally validate compound heterozygous variants in FBXL4 in a patient with generalised dystonia and dysmorphic facial features. Patient-derived iPSC will be used to complete this work.
L1CAM | Prof Vladimir Sytnyk, UNSW
In March 2023, Prof Vladimir Sytnyk at the University of NSW was awarded $60,000 to conduct functional studies for a family who had a stillborn child with multiple congenital anomalies and a variant of uncertain significance in L1CAM.
PPIL1 | Assoc Prof Quenten Schwarz, UniSA
Assoc Prof Quenten Schwarz at the University of South Australia was awarded $60,000 in May 2023 to investigate a VUS in PPIL1 that was discovered in a patient with global developmental delay, epileptic encephalopathy, microcephaly and general growth restriction.
Novel gene | Prof Stephen Fitter, University of Adelaide
Prof Stephen Fitter at the University of Adelaide will employ mouse modelling techniques to establish a novel gene disease association for a patient with skeletal malformation. Prof Fitter has been awarded $45,000 to support this work.
DNAI2 | Dr Nicole Shaw & Dr Vanessa Fear, Telethon Kids Institute
In October 2023, Dr Nicole Shaw at the Telethon Kids Institute at the University of Western Australia was awarded $60,000 to investigate a VUS in DNAI2 using gene editing in iPSCs and motile cilia modelling.
Novel gene | Dr Peter Howeling, Murdoch Children’s Research Institute
Dr Peter Houweling at the Murdoch Children’s Research Institute was awarded $30,000 in October 2023 to establish a novel gene disease association for a patient with frontonasal dysplasia. Research will involve investigations using mouse & patient-fibroblast lines.
NHLRC2 | Dr Rhiannon Werder, Murdoch Children’s Research Institute
In October 2023, Dr Rhiannon Werder at the Murdoch Children’s Research Institute was awarded $45,000 to investigate a VUS in NHLRC2 in a patient with tachypnoea and impaired swallowing using iPSC-lung models.
CREB3L2 | Prof Stephen Fitter, University of Adelaide
Prof Stephen Fitter at the University of Adelaide was awarded $45,000 in October 2023 to investigate a VUS in CREB3L2 found in a patient with skeletal dysplasia using a mouse model.
RPE65 | Prof Robyn Jamieson, University of Sydney
In January 2024, Prof Robyn Jamieson at the University of Sydney was awarded $60,000 to investigate variants in RPE65 found in a patient with retinal dystrophy using iPSC modelling.
Projects in this funding stream focus on investigating multiple VUS at a time in a known disease gene. The AFGN will prioritise genes with a high burden of VUSs and clinical need.
In round 1 we opened applications for the top 10 genes with the highest number of VUS in Shariant, a controlled access platform built to resolve discrepancies in variant interpretation between laboratories.
PKD1 | Prof Ian Smyth, Monash
Prof Smyth will work in collaboration with Dr Amali Mallawaarachchi, a nephrologist, clinical geneticist and biomedical researcher to functionally characterise and clinically interpret missense variants in the PKD1 gene associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD).
The project proposes to introduce VUS into the mouse germline using CRISPR technology and offspring will be examined for cyst development and disease progression. The study will focus on a subset of VUS which occur in functionally interesting parts of the protein to ascertain more knowledge of the function of POLYCYSTIN-1 and provide insights into VUS in nearby protein domains and which may assist in future functional assessment.
Key Metrics:
FLNC | Prof Robert Bryson-Richardson, Monash
In collaboration with Prof Diane Fatkin at the Victor Chang Cardiac Research Institute, Prof Robert Bryson-Richardson at Monash University will assess 10 benign and 20 known pathogenic FLNC variants in an early embryonic rescue assay that has been designed to complement data from their transgenic zebrafish lines. Benchmarking the embryonic assay using known variants will reduce reliance on transgenic strains and provide a more efficient and higher throughput for functional analysis of variants in FLNC associated with both cardiac and skeletal myopathy.
RYR1 | Dr Avnika Ruparelia, UoM
This research project, led by Avnika Ruparelia at the University of Melbourne, aims to investigate the gene RYR1 and its role in non-dystrophic congenital myopathy, a prevalent muscular disorder. This study will focus on 7 missense VUS spanning across multiple critical RYR1 domains including the N-terminal domain, junctional and solenoid domains, tandem repeat domains, and the transmembrane domain. Known benign and pathogenic controls will be used to set readout thresholds for normal and abnormal protein function.
TTN | Prof David Ascher, UQ
Mutations in TTN have been identified as common causes of inherited myopathies, affecting both heart and skeletal muscles. Prof David Ascher from the University of Queensland will investigate the potential role of rare missense variants as genetic modifiers that contribute to the phenotypic penetrance of dilated cardiomyopathy (DCM) and other related conditions. The study will employ a combination of biophysical and structural approaches, along with computational models, to evaluate the pathogenicity of TTN variants. By validating the developed platforms, the research team aims to provide evidence-based correlation to clinical parameters and facilitate risk assessment for individuals carrying these variants.
USH2A | Prof Robyn Jamieson, CMRI
Prof Robyn Jamieson at the Children’s Medical Research Centre will establish an isogenic allelic series of missense variants in USH2A in human-iPSC differentiated to retinal tissues. The series will include 4 missense VUS alongside 3 known pathogenic and 3 benign variants as controls. The project will focus on VUS associated with Usher syndrome type 2, the most common form, characterised by moderate to severe hearing abnormalities and onset of retinitis pigmentosa (RP) in the second decade.
ABCA4 | Prof Alex Hewitt, UTAS
Prof Alex Hewitt at the University of Tasmania will develop assays to evaluate the pathogenicity of missense, splice site and deep-intronic VUS in the ABCA4 gene associated with Stargardt disease and ABCA4-related cone-rod dystrophy. Given the number of emerging gene-based therapies for Stargardt disease and ABCA4- related cone-rod dystrophy, Prof Hewitt’s lab have designed a series of assays to facilitate the characterisation of all possible disease-causing variants. Missense variants will be assessed via an ATP binding assay will be performed, while for splice site and deep-intronic variants will be profiled using midigenes and RT-PCR analysis.