My career focus has been discovery and functional characterisation of variants that cause neurodevelopmental and neuromuscular disorders.

1. As an early adopter of massively parallel sequencing, my work has led directly to the implication of over 50 novel genes for neurodevelopmental disorders. I assisted in obtaining grant funding, provided bioinformatics support and training that enabled translating the use of this technology into molecular genetic testing at the Women’s and Children’s Hospital in Adelaide. The genes that we have discovered now contribute to gene panels used by molecular testing laboratories worldwide to diagnose others with these disorders. For example, PanelApp (Genomics England & Australia) and through indexing in the online Mendelian Inheritance in Man (OMIM) database (eg. #300953, #300957, #300979, #301024, #309590, #605021, #607876, #613608, #614018, #604364). Some examples of my key discoveries:

   1. Corbett MA, Bahlo M, Jolly L, Afawi Z, Gardner AE, Oliver KL, et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet. 2010 Sep 10;87(3):371–5. 

   2. Corbett MA, Schwake M, Bahlo M, Dibbens LM, Lin M, Gandolfo LC, et al. A Mutation in the Golgi Qb-SNARE Gene GOSR2 Causes Progressive Myoclonus Epilepsy with Early Ataxia. Am J Hum Genet. 2011 May 13;88(5):657–63. 

   3. Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, et al. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet. 2008 Feb;82(2):432–43. 

   4. Corbett MA, Dudding-Byth T, Crock PA, Botta E, Christie LM, Nardo T, et al. A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. J Med Genet. 2015 Apr;52(4):269–74. 

   5. Kumar R, Corbett MA, van Bon BWM, Woenig JA, Weir L, Douglas E, et al. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. Am J Hum Genet. 2015 Aug 6;97(2):302–10. 

   6. Corbett MA, Bellows ST, Li M, Carroll R, Micallef S, Carvill GL, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology. 2016 Oct 12;87(19):1975–84.

2. I have used RNA sequencing and prior to that, microarrays to show changes in gene expression patterns in patient cell lines that have given better understanding of disease processes and this has led to trials of clinical interventions. We have generated multiple gene expression and genomic sequencing datasets that are either available on request due to ethics requirements or where possible posted to the NCBI GEO or short read archive databases and contributed our variant discoveries to the ClinVar database. For much of my career, I took a collaborative role from within the Neurogenetics research team of Prof. Jozef Gecz where it was my responsibility to maintain the group's noted success in genomics at an international level. This required a constant need to innovate in one of fastest moving fields in biological research including building and maintaining our large neurodevelopmental genomics data resource of over 1000 exomes, 480 genomes, 579 RNA-Seq samples and 745 genotyping array samples.  Through this long-term commitment I contributed heavily to the continuous 15 year funding of the Epilepsy Research NHMRC program grants until the scheme ended (total research funding of that scheme: $52M AUD).

3. Turning my attention to the genetic basis of cerebral palsies (CP), I have shown that combined analysis of DNA and RNA sequencing shows 23% of cases have a genetic cause) in unselected cohorts. We developed a zebrafish model for CP and used it to demonstrate altered movement due to variants in novel genes we implicated in CP (PDCD6IP and WNT8B). My genomics and bioinformatics expertise was critical for our major studies in the field of CP genetics where our team has had an internationally leading role over the last decade. This pioneering work put the spotlight on the considerable underappreciated genetic contribution to CP; up to 30% of individuals with CP could receive a genetic diagnosis if offered testing.  This work breaks down a dogma where CP has traditionally been assumed to be due to environmental causes, or attributed to poor clinical management leading to inequity in access to genetic testing and subsequent lost opportunities for improved clinical management and development of precision therapies.

   1. Corbett MA, Eyk CL van, Webber DL, Bent SJ, Newman M, Harper K, et al. Pathogenic copy number variants that affect gene expression contribute to genomic burden in cerebral palsy. npj Genomic Medicine. 2018 Dec 14;3(1):33.

   2. McMichael G, Bainbridge MN, Haan E, Corbett M, Gardner A, Thompson S, et al. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry. 2015 Feb 10;20(2):176–82.

   3. van Eyk CL, Corbett MA, Gardner A, van Bon BW, Broadbent JL, Harper K, et al. Analysis of 182 cerebral palsy transcriptomes points to dysregulation of trophic signalling pathways and overlap with autism. Transl Psychiatry. 2018 Apr 23;8(1):88.

   4. van Eyk CL, Corbett MA, Frank MSB, Webber DL, Newman M, Berry JG, et al. Targeted resequencing identifies genes with recurrent variation in cerebral palsy. NPJ Genom Med. 2019;4:27.

   5. Kayumi S, Pérez-Jurado LA, Palomares M, Rangu S, Sheppard SE, Chung WK, et al., Corbett MA. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genet Med. 2022 Sep 9;24(11):2351–66.

   6. Jin SC, Lewis SA, Bakhtiari S, Zeng X, Sierant MC, Shetty S, … , Corbett MA, et al. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nat Genet. 2020 Oct;52(10):1046–56.

4. I have always considered regulatory variants as a likely missed cause in genetically unresolved neurodevelopmental disorders. I have had leading roles and published multiple non-coding variants implicated in intellectual disability and epilepsy using massively parallel sequencing combined with gene expression studies. I discovered a novel repeat expansion motif  in the STARD7 gene that causes familial adult onset myoclonic epilepsy “FAME”.  This work has positively impacted over 200 individuals from 27 families worldwide. Pathogenic FAME repeats occur at eight different chromosomal loci, seven cause FAME and one causes SCA37.

   1. Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R, Douglas E, et al. Corbett MA, Gecz J A Noncoding, Regulatory Mutation Implicates HCFC1 in Nonsyndromic Intellectual Disability. Am J Hum Genet. 2012 Sep 18;91(4):694–702. 

   2. Haines B, Hughes J, Corbett M, Shaw M, Innes J, Patel L, et al. Interchromosomal Insertional Translocation at Xq26.3 Alters SOX3 Expression in an Individual With XX Male Sex Reversal. J Clin Endocrinol Metab. 2015 May;100(5):E815-820. 

   3. Kumar R, Ha T, Pham D, Shaw M, Mangelsdorf M, Friend KL, et al. Corbett M, Gecz J. A non-coding variant in the 5’ UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability. Eur J Hum Genet. 2016 May 25;24(11):1612–6. 

   4. Corbett MA, Kroes T, Veneziano L, Bennett MF, Florian R, Schneider AL, et al. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun. 2019 Oct 29;10(1):4920.

   5. 5. Florian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, et al. Corbett MA, … , Depienne C Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nat Commun. 2019 Oct 29;10(1):4919. 

   6. Field MJ, Kumar R, Hackett A, Kayumi S, Shoubridge CA, Ewans LJ, et al. Corbett MA. Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability. Hum Mutat. 2021 Apr 13;42(7):835–47.