The Bahlo lab works on two retinal disorders: Macular Telangiectasia Type 2 (MacTel) and Age-related Macular Degeneration (AMD). Using genome-wide association analysis (GWAS) methods for both diseases we discovered the first loci for MacTel in 2017. In recent years we have combined genomic data with metabolomic data as well as analysing and further combining extensive data generated by collaborators from the MacTel consortium. In the past two years the Bahlo lab has started a collaboration to work on a subtype of AMD with poorer prognostic outcome. This will involve using GWAS and related methods to investigate the genetic basis of this AMD subtype.

Prof Melanie Bahlo AM, Lab Head | WEHI Researcher Profile

Q: Genetics of speech disorders

One in five Australian children start school with a speech or language disorder. While some children will grow out of it, many others will go on to have persistent speech difficulties. Such disorders can have a profound effect on an individual’s social and mental wellbeing. Speech disorders are thought to be caused by a combination of genetic, neurological and environmental factors. Understanding more about the genetic causes of speech disorders may improve developments in treatment and help us to identify individuals most at risk of these disorders. In this project, we take several approaches to investigate the genetics underlying speech problems. Through whole exome and whole genome sequencing (WES/WGS) of families, we have identified causal variants responsible for rare forms of familial speech disorders. We are working to assemble an international cohort of people who stutter, with which we shall undertake a genome-wide association study (GWAS) to identify common genetic variation, influencing risk of stuttering in the general population.

Q: Detecting repeat expansions

Short tandem repeats are short repetitive elements of the genome, which can vary in length between individuals. Some repeats are unstable and can expand in length. Repeat expansions cause a number of neurological disorders, such as Huntington's disease and spinocerebellar ataxias as well as other more common neurological disorders, such as epilepsy and motor neuron disease. Identifying repeat expansions is difficult as their length can greatly exceeds the read lengths of short read sequencing. Standard clinical tests are specialised and expensive and not routinely performed for the majority of patients. The Bahlo lab has developed new methods to identify repeat expansions in whole exome and whole genome sequencing data. We are interested in searching for known or novel repeat expansions associated with a variety of neurological disorders and indeed have discovered novel repeat expansions. Our work has also provided diagnosis for patients where it had previously not been possible to detect repeat expansions, even though they were the cause of their disorders.

Q: Identity by descent methods and applications

Genomic regions that are inherited from a common ancestor are said to be identical by descent (IBD). Identification of such regions has proven useful in human studies with application including discovery of familial relatedness, disease mapping and determining loci under selection. The Bahlo lab has developed multiple implementations of IBD methods including: - IBD methods applicable to the X-chromosome, a special case - IBD methods to mixed samples, such as those seen in microorganisms that recombine and multiply infect humans, for example those that cause malaria. The Bahlo lab has published many applications of IBD methods to refine the genomic location of disease-causing variants.

Q: Genome-wide association study investigations

The Bahlo lab has been involved and also led several genome-wide association studies (GWAS) and has previously worked on X chromosome analysis methods, as well as demonstrating that saliva derived DNA achieves high quality data of an equivalent standard to that derived from blood samples. We are continuing to perform GWAS studies in AMD, MacTel and stuttering, combining these basic analyses with techniques such as expression QTL and metabolomic QTL studies making use of modern analysis methods such as Mendelian Randomisation. The lab is also applying these methods to epilepsy through collaborations with the International League against Epilepsy (ILAE) consortium.

Q: Genomics to accelerate precision dementia research

Dementia is a heterogeneous disorder with many different subtypes that are driven by dysregulation of biological pathways. Treatment selection for dementias is based on subtype, but accurate diagnosis in the clinical setting is very challenging early on in the disease when therapies have their greatest potential. Vast improvement in dementia diagnostics is required for truly targeted treatments. We aim to supercharge dementia research by overlaying personalised genomics to WEHI’s current and future multi-disciplinary dementia projects. Conducting whole genome sequencing on patients and analysing the data will help tease apart this heterogenous patient cohort, providing greater understanding of dementia sub-types and facilitate more suitable selection of clinical trials and therapies. It will also reveal if women are genetically pre-disposed to developing dementia. Furthermore, working closely with the experts above and combining their projects’ data with the genomics information will generate an enormous, complex, and critical data set on dementia. This invaluable resource will fast track our biomarker development and diagnostic tests, advance our understanding of the disease to help identify potential targets for therapeutic development, and likely aid prognosis. This four-year project launched with a $1million flagship grant from the Alfred Felton Bequest will involve conducting whole genome sequencing on 500 Victorian patients (recruited via Royal Melbourne Hospital, the Alfred Hospital, and others), then performing comprehensive data analysis on those results, as well as other WEHI dementia projects, to facilitate precision dementia research.

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Our lab uses statistical methodology to describe and model genetic data, by identifying and making use of structure within the data. This pinpoints genomic regions that may harbor disease-causing mutations, as well as provide insight into disease pathogenesis. We implement these models through software development and bespoke data analyses, primarily in the R programming language.

We work on many disease identification projects concurrently, some of which can be readily solved with existing methods and analytic pipelines. Others may prove more challenging, potentially taking years of development and analysis before a breakthrough is achieved. We seek to identify when and where new technologies can be implemented to achieve breakthroughs in studies that have remained unsolved thus far.

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Selected publications from Prof Melanie Bahlo AM

Rafehi H, Fearnley LG, Read J, Snell P, Davies KC, Scott L, Gillies G, Thompson GC, Field TA, Eldo A, Bodek S, Butler E, Chen L, Drago J, Goel H, Hackett A, Halmagyi GM, Hannaford A, Kotschet K, Kumar KR, Kumble S, Lee-Archer M, Malhotra A, Paine M, Poon M, Pope K, Reardon K, Ring S, Ronan A, Silsby M, Smyth R, Stutterd C, Wallis M, Waterston J, Wellings T, West K, Wools C, Wu KHC, Szmulewicz DJ, Delatycki MB, Bahlo M, Lockhart PJ. A prospective trial comparing programmable targeted long-read sequencing and short-read genome sequencing for genetic diagnosis of cerebellar ataxia.Genome Research. 2025;35(4):10.1101/gr.279634.124

Gambardella A, Liu Y, Bennett MF, Green TE, Damiano JA, Fortunato F, Coleman MJ, Cherfils J, Barnier J, Gecz J, Bahlo M, Berkovic SF, Hildebrand MS. PAK3 pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism. Epilepsia Open. 2025;10(2):10.1002/epi4.13124

Robertson E, Grinton BE, Oliver KL, Fearnley LG, Hildebrand MS, Sadleir LG, Scheffer IE, Berkovic SF, Bennett MF, Bahlo M. Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data. NAR Genomics and Bioinformatics. 2025;7(2):10.1093/nargab/lqaf033

Munro JE, Coussens AK, Bahlo M. TBtypeR: Sensitive detection and sublineage classification of Mycobacterium tuberculosis complex mixed-strain infections. Communications Biology. 2025;8(1):10.1038/s42003-025-07705-9

Rayner G, Honybun E, Bahlo M, Oliver KL, Scheffer IE. Psychoses of Epilepsy: Unravelling the Phenotypic and Genotypic Features. Annals of Neurology. 2025;:10.1002/ana.27209

Jackson VE, Wu Y, Bonelli R, Owen JP, Scott LW, Farashi S, Kihara Y, Gantner ML, Egan C, Williams KM, Ansell BRE, Tufail A, Lee AY, Bahlo M. Multi-omic spatial effects on high-resolution AI-derived retinal thickness. Nature Communications. 2025;16(1):10.1038/s41467-024-55635-7

Han J, Gerring ZF, Wang L, Bahlo M. GeneSetPheno: a web application for the integration, summary, and visualization of gene and variant–phenotype associations across gene sets. Bioinformatics Advances. 2024;5(1):10.1093/bioadv/vbaf078

Davies KC, Fearnley LG, Snell P, Bourke D, Mossman S, Kyne K, McKeown C, Delatycki MB, Bahlo M, Lockhart PJ. A multi-exon RFC1 deletion in a case of CANVAS: expanding the genetic mechanism of disease. Journal of Neurology. 2024;271(12):10.1007/s00415-024-12675-9

Chaar WA, Eranki AN, Stevens HA, Watson SL, Wong DY, Avila VS, Delfeld M, Gary AJ, Tawde S, Triebold M, Cherchi M, Xie T, Lockhart PJ, Bahlo M, Pellerin D, Dicaire M, Danzi M, Zuchner S, Brais BC, Perlman S, Burmeister M, Paulson H, Srinivasan S, Schut L, Bower M, Bushara K, Liao C, Shakkottai VG, Collins J, Clark HB, Das S, Fogel BL, Gomez CM. Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Annals of Neurology. 2024;96(6):10.1002/ana.27060

Wang L, Han J, Fearnley LG, Milton M, Rafehi H, Reid J, Gerring ZF, Masaldan S, Lang T, Speed TP, Bahlo M. Peripheral immune cell abundance differences link blood mitochondrial DNA copy number and Parkinson’s disease. npj Parkinson’s Disease. 2024;10(1):10.1038/s41531-024-00831-x

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Lab research projects

Genetics of speech disorders

Detecting repeat expansions

Retinal disorders

Identity by descent methods and applications

Genome-wide association study investigations

Genomics to accelerate precision dementia research

Prof Melanie Bahlo AM

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