Funding opportunity: FxGx platforms to assess multiple VUS in priority genes

The AFGN has announced a second round of funding to establish functional genomics platforms to assess multiple variants of uncertain significance (VUS) in priority genes.
Submit an EOI

Expressions of interest close: Friday October 11th 2024

Many known and novel disease genes have significant numbers of potentially disease-causing variants that do not meet the current threshold for a definitive genetic diagnosis. Parallel assessments of these genetic variants’ functional consequences can enhance our understanding of the underlying genetic basis of disease.

The following gene-list represents the genes that have been indicated as high priority genes for variant resolution by Australian diagnostic laboratories and clinicians.

GENE

DISEASE ASSOCIATION

CLINVAR

# of VUS

(% of VUS)
MYH7

Myosin Heavy Chain 7

 Cardiomyopathy & Myopathy

2184
(60%)
MYBPC3

Myosin Binding Protein C, Cardiac

 Cardiomyopathy

1941
(50%)
RP1L1

Retinitis Pigmentosa 1-Like 1

 Retinitis pigmentosa & Macular dystrophy

690
(61%)
DNAH11

Dynein Axonemal Heavy Chain 11

 Primary ciliary dyskinesia (Ciliopathy)

1308
(24%)
CDH23

Cadherin-Related 23

 Usher syndrome (deafness, reduced vestibular function, retinal degeneration), Deafness (AR) & Pituitary adenoma

1692
(35%)
MYO7A

Myosin VIIA

 Deafness (AD & AR), Usher syndrome

1432
(34%)
DSP

Desmoplakin

 Arrhythmogenic cardiomyopathy with wooly hair and keratoderma & Arrhythmogenic right ventricular dysplasia

2688
(56%)
KMT2D

Lysine Methyltransferase 2D

 Kabuki syndrome (multisystem disorder including facial, neurological & cardiac malformations)

1893
(37%)
COL4A4

Collagen Type IV Alpha 4 Chain

 Kidney disease (Alport syndrome & Hematuria)

759
(27%)
LDLR

Low-Density Lipoprotein Receptor

 Familial hypercholesterolemia

1075
(33%)
SMAD4

SMAD Family Member 4

 Juvenile polyposis, hereditary hemorrhagic telangiectasia syndrome (blood vessel malformations) & Myhre syndrome (connective tissue disorder)

1085
(52%)
ENG

Endoglin

 Hereditary hemorrhagic telangiectasia syndrome (blood vessel malformations)

344
(33%)
ACVRL1

Activin A Receptor Like Type 1

 Hereditary hemorrhagic telangiectasia syndrome

257
(27%)
FBN1

Fibrillin-1

 Connective tissue disorders including Marfan syndrome

2685
(39%)
CFH

Complement Factor H

 Blood disorders including hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy

411
(53%)
IDH2

Isocitrate Dehydrogenase 2

 Neurometabolic disorder (D-2-hydroxyglutaric aciduria)

97
(50%)
COL6A3

Collagen Type VI Alpha 3 Chain

 Bethlem Myopathy, Dystonia &
Ullrich Congenital Muscular Dystrophy

1893
(59%)
SQSTM1

Sequestosome 1

 Frontotemporal dementia and/or amyotrophic lateral sclerosis, distal myopathy, childhood-onset neurodegeneration & Paget disease of bone

355
(53%)
ARID1B

AT-Rich Interaction Domain 1B

 Coffin-Siris Syndrome (Multiple malformation syndrome)

615
(36%)
ARID1A

AT-Rich Interaction Domain 1A

 Coffin-Siris Syndrome

468
(44%)
GCK

Glucokinase

 Diabetes mellitius including Maturity onset diabetes of the young (MODY) type 2,
late onset noninsulin-dependent, permanent neonatal & familial hyperinsulinemic hypoglycemia

416
(48%)
HNF1A

Hepatocyte Nuclear Factor 1 Alpha

 Insulin-dependent diabetes mellitus, MODY type 3 & renal cell carcinoma

285
(42%)

 

Application procedure

Step 1: Review the high-priority gene list and select your genes of interest via the REDCap survey.

Step 2: Receive a list of VUS from diagnostic labs for inclusion in your platform proposal within 2-6 weeks of submission.

Step 3: Submit your full proposal within 4 weeks of receiving the variant list using the form provided.

Step 4: Applications will be reviewed by the AFGN Scientific Review Committee.

Submit an EOI

We will prioritise proposals for platforms that:

  • Are already established and scalable; however new platforms are also welcomed.
  • Achieve clinically relevant turnaround (6-12 months).
  • Leverage appropriate expertise as well as cash and/or in-kind contribution.
  • Have the potential to be cost efficient and scaled to resolve multiple VUS identified through diagnostic testing in the future.
Preview submission form

Budget:

No minimum amount is set for a single grant. The maximum funding for a single grant is $200,000. Budgets will be evaluated based on the complexity of the platform and number of variants being analysed.

Project design:

Applications should consider the stringency of evidence required to elevate a variant from VUS (3) to likely pathogenic/pathogenic (4/5) in their proposal (see Brnich et al. Genome Medicine (2020) 12:3).

We encourage the use of existing resources. Phenomics Australia, an NCRIS-funded initiative, offers expertise in developing disease models.

For more information, contact John Parisot at j.parisot@therapeuticinnovation.com.au or visit:

In Vivo Genome Engineering & Disease Modelling

In Vitro Genome Engineering & Disease Modelling Service

 

Enquiries can be directed to: functional.genomics@mcri.edu.au.

Download round 2 gene list