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4. POT1and multiple primary melanomas: the dermatological phenotype

Author

Maas, Ellie J, primary, DeBortoli, Emily, additional, Nathan, Vaishnavi, additional, Freeman, Ned P, additional, Mothershaw, Adam, additional, Smit, Darren J, additional, Betz-Stablein, Brigid, additional, Aoude, Lauren G, additional, Stark, Mitchell S, additional, Sturm, Richard A, additional, Soyer, H Peter, additional, and McInerney-Leo, Aideen M, additional

Published
2024
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7. Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Author

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R, McInerney-Leo, Aideen M, Emes, Richard D, Arts, Heleen H, Tüysüz, Beyhan, D’Silva, Jason, Leo, Paul J, Giles, Tom C, Oud, Machteld M, Harris, Jessica A, Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T, Wilson, Louise C, Janecke, Andreas R, Hurles, Matthew E, Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J, Brown, Matthew A, Beales, Philip L, Wicking, Carol, UK10K, Duncan, Emma L, and Mitchison, Hannah M

Subjects
Rare Diseases, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Asians, Axoneme, Carrier Proteins, Child, Chlamydomonas, Cilia, Cytoplasmic Dyneins, Cytoskeleton, Ellis-Van Creveld Syndrome, Exome, Exons, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Mutation, Protein Conformation, Proteomics, Whites, UK10K, Asian People, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Published
2013

9. The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence.

Author

Atkinson, Caroline, McInerney-Leo, Aideen M., Proctor, Martina, Lanagan, Catherine, Stevenson, Alexander J., Dehkhoda, Farhad, Caole, Mary, Maas, Ellie, Ainger, Stephen, Pritchard, Antonia L., Johansson, Peter A., Leo, Paul, Hayward, Nicholas K., Sturm, Richard A., Duncan, Emma L., and Gabrielli, Brian

Subjects
*DNA repair, *DNA damage, *ONCOGENES, *AUTOMATED teller machines, *PROTEIN kinases, *GENE frequency
Abstract

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Rare and common variants in GALNT3 may affect bone mass independently of phosphate metabolism

Author

Hassan, Neelam, Gregson, Celia L., Tang, Haotian, van der Kamp, Marc W., Leo, Paul, McInerney-Leo, Aideen M., Zheng, Jie, Brandi, Maria Luisa, Tang, Jonathan C. Y., Fraser, William, Stone, Michael D., Grundberg, Elin, Brown, Matthew A., Duncan, Emma L., and Tobias, Jonathan H.

Subjects
Endocrinology, Diabetes and Metabolism, Orthopedics and Sports Medicine
Abstract

Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C>T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831T>A, p.Asp277Glu) within the same gene. In silico protein modelling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3; and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or co-receptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and GWAS data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, identification of which may yield novel anabolic drug targets for osteoporosis.

Published
2023

12. MITF E318K: A rare homozygous case with multiple primary melanoma.

Author

Wallingford, Courtney K., Maas, Ellie J., Howard, Antonia, DeBortoli, Emily, Bhanja, Deboshmita, Lee, Katie, Mothershaw, Adam, Jagirdar, Kasturee, Willett, Rod, Betz‐Stablein, Brigid, Sturm, Richard A., Soyer, H. Peter, and McInerney‐Leo, Aideen M.

Subjects
MELANOMA, NEVUS, HOMOZYGOSITY, HETEROZYGOSITY, PHENOTYPES, NECK
Abstract

MITF E318K moderates melanoma risk. Only five MITF E318K homozygous cases have been reported to date, one in association with melanoma. This novel report uses 3D total‐body‐photography (TBP) to describe the dermatological phenotype of a homozygous MITF E318K individual. The case, a 32‐year‐old male, was diagnosed with his first of six primary melanomas at 26 years of age. Five melanomas were located on the back and one in the groin. Two were superficial spreading. Three arose from pre‐existing naevi and one was a rare naevoid melanoma. 3D‐TBP revealed a high naevus count (n = 162) with pigmentation varying from light to dark. Most naevi generally (n = 90), and large (>5 mm diameter) and clinically atypical naevi specifically were located on the back where sun damage was mild. In contrast, naevi count was low (n = 25 total) on the head/neck and lower limbs where sun damage was severe. Thus, melanoma location correlated with naevi density, rather than degree of sun damage. In addition to the MITF E318K homozygosity, there was heterozygosity for four other moderate‐risk variants, which may contribute to melanoma risk. Further research is warranted to explore whether melanomas in E318K heterozygous and other homozygotes coincide with regions of high naevi density as opposed to sun damage. This could inform future melanoma screening/surveillance. [ABSTRACT FROM AUTHOR]

Published
2024
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13. The MC1R r allele does not increase melanoma risk in MITF E318K carriers

Author

Wallingford, Courtney K, primary, Demeshko, Anastassia, additional, Krishnakripa, Asha Krishnankutty, additional, Smit, Darren J, additional, Duffy, David L, additional, Betz-Stablein, Brigid, additional, Pflugfelder, Annette, additional, Jagirdar, Kasturee, additional, Holland, Elizabeth, additional, Mann, Graham J, additional, Primiero, Clare A, additional, Yanes, Tatiane, additional, Malvehy, Josep, additional, Badenas, Cèlia, additional, Carrera, Cristina, additional, Aguilera, Paula, additional, Olsen, Catherine M, additional, Ward, Sarah V, additional, Haass, Nikolas K, additional, Sturm, Richard A, additional, Puig, Susana, additional, Whiteman, David C, additional, Law, Matthew H, additional, Cust, Anne E, additional, Potrony, Miriam, additional, Soyer, H Peter, additional, and McInerney-Leo, Aideen M, additional

Published
2023
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14. Genomics predicting prognosis in metastatic extramammary Paget disease.

Author

McInerney-Leo, Aideen M and McMeniman, Erin K

Subjects
*POLY ADP ribose, *OVERALL survival, *PROGRESSION-free survival, *MEDICAL fellowships, *SURVIVAL analysis (Biometry)
Abstract

The article discusses extramammary Paget disease (EMPD), a rare cutaneous neoplasm that primarily affects apocrine-rich skin regions. It highlights the importance of cancer genomic profiling (CGP) in predicting prognosis and treatment outcomes for EMPD patients. The study by Iwasawa et al. focuses on identifying CDKN2A and BRCA2 variants in secondary EMPD cases, showing a correlation between these variants and poorer prognosis. The research suggests that genomically matched therapies may improve outcomes for EMPD patients, emphasizing the need for further comprehensive genomic studies in this field. [Extracted from the article]

Published
2025
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15. Final Stakeholder Report of the Australian Genetics and Life Insurance Moratorium: Monitoring the Effectiveness and Response (A-GLIMMER) Project

Author

Tiller, Jane, Gleeson, Penny, McInerney-Leo, Aideen M., Keogh, Louise, Nowak, Kristen, Barlow-Stewart, Kristine, Boughtwood, Tiffany, Delatycki, Martin B., Winship, Ingrid, Otlowski, Margaret, and Lacaze, Paul

Subjects
Law and society and socio-legal research, Public health not elsewhere classified, Genomics, Medical ethics, Health policy
Abstract

In 2018, a Joint Parliamentary Committee Inquiry into the Life Insurance Industry recommended that Australia urgently implement a moratorium (or ban) on the use of genetic test results in life insurance underwriting. In 2019, the life insurance industry introduced a partial moratorium requiring applicants to disclose genetic test results only for policies above certain financial limits. This moratorium is industry self-regulated, with no government oversight. To investigate effectiveness of the moratorium as a regulatory solution to genetic discrimination in Australian life insurance, the Commonwealth Government funded the Australian Genetics and Life Insurance Moratorium: Monitoring the Effectiveness and Response (A-GLIMMER) Project from 2020- 2023. This Final Stakeholder Report sets out the A-GLIMMER Project findings – published and unpublished – and makes recommendations to the Australian Government (the Project funder). The studies undertaken as part of the Project investigated the views and experiences of health professionals, consumers, researchers, and financial advisors. The A-GLIMMER Project’s research findings demonstrate that the moratorium is inadequate to address and prevent genetic discrimination in life insurance. It should be replaced with a legislative model of prohibition. The A-GLIMMER Project recommends that: 1. The Australian Government amend the Disability Discrimination Act 1992 (Cth) (‘the Act’) to prohibit insurers from using genetic or genomic test results to discriminate between applicants for risk-rated insurance, and consider amendments to the regulation of financial services to ensure insurers are subject to a positive duty to not discriminate. 2. The Australian Government allocate responsibility and appropriate resources to the Australian Human Rights Commission (‘AHRC’) to enforce, promote, educate and support individuals and all relevant stakeholders to understand and meet the new legal obligations under the Act. The AHRC should consult with a range of genetics and genomics experts and stakeholders to achieve this goal.

Published
2023
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17. Australian human research ethics committee members’ confidence in reviewing genomic research applications

Author

Pysar, Ryan, Wallingford, Courtney K., Boyle, Jackie, Campbell, Scott B., Eckstein, Lisa, McWhirter, Rebekah, Terrill, Bronwyn, Jacobs, Chris, and McInerney-Leo, Aideen M.

Abstract

Human research ethics committees (HRECs) are evaluating increasing quantities of genomic research applications with complex ethical considerations. Genomic confidence is reportedly low amongst many non-genetics-experts; however, no studies have evaluated genomic confidence levels in HREC members specifically. This study used online surveys to explore genomic confidence levels, predictors of confidence, and genomics resource needs of members from 185 HRECs across Australia. Surveys were fully or partially completed by 145 members. All reported having postgraduate 94 (86%) and/or bachelor 15 (14%) degrees. Participants consisted mainly of researchers (n= 45, 33%) and lay members (n= 41, 30%), affiliated with either public health services (n= 73, 51%) or public universities (n= 31, 22%). Over half had served their HREC ≥3 years. Fifty (44%) reviewed genomic studies ≤3 times annually. Seventy (60%) had undertaken some form of genomic education. While most (94/103, 91%) had high genomic literacy based on familiarity with genomic terms, average genomic confidence scores (GCS) were moderate (5.7/10, n= 119). Simple linear regression showed that GCS was positively associated with years of HREC service, frequency of reviewing genomic applications, undertaking self-reported genomic education, and familiarity with genomic terms (p< 0.05 for all). Conversely, lay members and/or those relying on others when reviewing genomic studies had lower GCSs (p< 0.05 for both). Most members (n= 83, 76%) agreed further resources would be valuable when reviewing genomic research applications, and online courses and printed materials were preferred. In conclusion, even well-educated HREC members familiar with genomic terms lack genomic confidence, which could be enhanced with additional genomic education and/or resources.

Published
2024
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18. The congenital hearing phenotype in GJB2in Queensland, Australia: V37I and mild hearing loss predominates

Author

Kriukelis, Rebecca, Gabbett, Michael T., Beswick, Rachael, McInerney-Leo, Aideen M., Driscoll, Carlie, and Liddle, Karen

Abstract

GJB2was originally identified in severe, non-syndromic sensorineural hearing loss (SNHL), but was subsequently associated with mild and moderate SNHL. Given the increasing utilisation of genetic testing pre-conceptually, prenatally, and neonatally, it is crucial to understand genotype-phenotype correlations. This study evaluated the nature and frequency of GJB2 variants in an Australian paediatric population with varying degrees of SNHL ascertained through newborn hearing screening. Audiograms from individuals with GJB2variants and/or a GJB6deletion (GJB6-D13S11830) were retrospectively reviewed (n= 127). Two-thirds were biallelic (homozygous/compound heterozygous) for pathogenic/likely pathogenic variants of GJB2and/or GJB6(n= 80). The most frequent variant was c.109 G > A, followed by c.35delG and c.101 T > C. Compared to biallelic carriage of other GJB2variants, c.109 G > A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial and latest audiograms (p= 0.0004). Biallelic carriage of c.35delG was associated with moderately-severe or greater SNHL at both initial and latest audiograms (p= 0.007). The c.101 T > C variant presented with milder SNHL and U-shaped audiograms (p= 0.02). In this agnostically identified cohort, mild SNHL predominated in GJB2/GJB6carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109 G > A, associated with milder phenotypes, was the most frequent. This study provides valuable data to support prognostic confidence in genetic counselling.

Published
2024
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19. Attitudes of Australian dermatologists on the use of genetic testing: A cross-sectional survey with a focus on melanoma

Author

Primiero, Clare A., primary, Baker, Amy M., additional, Wallingford, Courtney K., additional, Maas, Ellie J., additional, Yanes, Tatiane, additional, Fowles, Lindsay, additional, Janda, Monika, additional, Young, Mary-Anne, additional, Nisselle, Amy, additional, Terrill, Bronwyn, additional, Lodge, Jason M., additional, Tiller, Jane M., additional, Lacaze, Paul, additional, Andersen, Hayley, additional, McErlean, Gemma, additional, Turbitt, Erin, additional, Soyer, H. Peter, additional, and McInerney-Leo, Aideen M., additional

Published
2022
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22. Community input in a genomic health implementation program: Perspectives of a community advisory group

Author

Vidgen, Miranda E., primary, Cutler, Katrina, additional, Bean, Jessica, additional, Bunker, David, additional, Fowles, Lindsay F., additional, Healy, Louise, additional, Hondow, Gary, additional, Istiko, Satrio Nindyo, additional, McInerney-Leo, Aideen M., additional, Pratt, Gregory, additional, Robins, Deborah, additional, Waddell, Nicola, additional, and Evans, Erin, additional

Published
2022
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23. Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial

Author

Chang, Anne B, primary, Morgan, Lucy C, additional, Duncan, Emma L, additional, Chatfield, Mark D, additional, Schultz, André, additional, Leo, Paul J, additional, McCallum, Gabrielle B, additional, McInerney-Leo, Aideen M, additional, McPhail, Steven M, additional, Zhao, Yuejen, additional, Kruljac, Catherine, additional, Smith-Vaughan, Heidi C, additional, Morris, Peter S, additional, Marchant, Julie M, additional, Yerkovich, Stephanie T, additional, Cook, Anne L, additional, Wurzel, Danielle, additional, Versteegh, Lesley, additional, O’Farrell, Hannah, additional, McElrea, Margaret S, additional, Fletcher, Sabine, additional, D'Antoine, Heather, additional, Stroil-Salama, Enna, additional, Robinson, Phil J, additional, and Grimwood, Keith, additional

Published
2022
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24. Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial

Author

Chang, Anne, Morgan, Lucy, Duncan, Emma, Chatfield, Mark D., Schultz, Andre, Leo, Paul, McCallum, Gabrielle Britt, McInerney-Leo, Aideen M., McPhail, Steven, Zhao, Yuejen, Kruljac, Catherine, Smith-Vaughan, Heidi C., Morris, Peter Stanley, Marchant, Julie, Yerkovich, Stephanie, Cook, Anne, Wurzel, Danielle F., Versteegh, Lesley, O'Farrell, Hannah, McElrea, Margaret, Fletcher, Sabine, D'Antoine, Heather, Stroil-Salama, Enna, Robinson, Phil, Grimwood, Keith, Chang, Anne, Morgan, Lucy, Duncan, Emma, Chatfield, Mark D., Schultz, Andre, Leo, Paul, McCallum, Gabrielle Britt, McInerney-Leo, Aideen M., McPhail, Steven, Zhao, Yuejen, Kruljac, Catherine, Smith-Vaughan, Heidi C., Morris, Peter Stanley, Marchant, Julie, Yerkovich, Stephanie, Cook, Anne, Wurzel, Danielle F., Versteegh, Lesley, O'Farrell, Hannah, McElrea, Margaret, Fletcher, Sabine, D'Antoine, Heather, Stroil-Salama, Enna, Robinson, Phil, and Grimwood, Keith

Abstract

Introduction: Primary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving children and adults with PCD and thus evidence of efficacy for interventions are usually extrapolated from people with cystic fibrosis. Our planned RCT seeks to address some of these unmet needs by employing a currently prescribed (but unapproved for long-term use in PCD) macrolide antibiotic (azithromycin) and a novel mucolytic agent (erdosteine). The primary aim of our RCT is to determine whether regular oral azithromycin and erdosteine over a 12-month period reduces acute respiratory exacerbations among children and adults with PCD. Our primary hypothesis is that: people with PCD who regularly use oral azithromycin and/or erdosteine will have fewer exacerbations than those receiving the corresponding placebo medications. Our secondary aims are to determine the effect of the trial medications on PCD-specific quality-of-life (QoL) and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations) and nasopharyngeal bacterial carriage and antimicrobial resistance. Methods and analysis: We are currently undertaking a multicentre, double-blind, double-dummy RCT to evaluate whether 12 months of azithromycin and/or erdosteine is beneficial for children and adults with PCD. We plan to recruit 104 children and adults with PCD to a parallel, 2×2 partial factorial superiority RCT at five sites across Australia. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, lung function and nasopharyngeal carriage by respiratory bacterial pathogens and their associated azithromycin resistance. Ethics and dissemination: Our RCT is conducted in accordance with Good Clinical Practice and the Australian legislation and National Health and Medical Research C

Published
2022

25. Evaluation of a Genetics Education Program for Health Interpreters: A Pilot Study

Author

Vidgen, Miranda E., primary, Fowles, Lindsay F., additional, Istiko, Satrio Nindyo, additional, Evans, Erin, additional, Cutler, Katrina, additional, Sullivan, Kate, additional, Bean, Jessica, additional, Healy, Louise, additional, Hondow, Gary, additional, McInerney-Leo, Aideen M., additional, Pratt, Gregory, additional, Robins, Deborah, additional, Best, Stephanie, additional, Finlay, Keri, additional, Ramarao-Milne, Priya, additional, and Waddell, Nicola, additional

Published
2022
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27. Human Genetics Society of Australasia Position Statement: Genetic Testing and Personal Insurance Products in Australia.

Author

DeBortoli, Emily, McInerney-Leo, Aideen M., Ayres, Samantha, Boyle, Jackie, Jacobs, Chris, and Newson, Ainsley J.

Subjects
*GENETIC testing, *LIFE insurance, *HUMAN genetics, *LIFE insurance policies, *INSURANCE, *IMPACT testing, *PHARMACOGENOMICS, *GENETICS
Abstract

The expansion of genetic and genomic testing in clinical practice and research, and the growing market for direct-to-consumer genomic testing has led to increased awareness about the impact of this form of testing on insurance. Genetic or genomic information can be requested by providers of mutually rated insurance products, who may then use it when setting premiums or determining eligibility for cover under a particular product. Australian insurers are subject to relevant legislation and an industry led standard that was updated in 2019 to introduce a moratorium on the use of genetic test results in life insurance underwriting for policies

Published
2023
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28. The Future of Precision Prevention for Advanced Melanoma

Author

Lee, Katie J., primary, Betz-Stablein, Brigid, additional, Stark, Mitchell S., additional, Janda, Monika, additional, McInerney-Leo, Aideen M., additional, Caffery, Liam J., additional, Gillespie, Nicole, additional, Yanes, Tatiane, additional, and Soyer, H. Peter, additional

Published
2022
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33. A step forward, but still inadequate: Australian health professionals’ views on the genetics and life insurance moratorium

Author

Tiller, Jane M, primary, Keogh, Louise A, additional, McInerney-Leo, Aideen M, additional, Belcher, Andrea, additional, Barlow-Stewart, Kristine, additional, Boughtwood, Tiffany, additional, Gleeson, Penny, additional, Dowling, Grace, additional, Prince, Anya, additional, Bombard, Yvonne, additional, Joly, Yann, additional, Delatycki, Martin, additional, Winship, Ingrid M, additional, Otlowski, Margaret, additional, and Lacaze, Paul, additional

Published
2021
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34. Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB’s role in oncogenesis

Author

McInerney-Leo, Aideen M, primary, Chew, Hui Yi, additional, Inglis, Po-Ling, additional, Leo, Paul J, additional, Joseph, Shannon R, additional, Cooper, Caroline L, additional, Okano, Satomi, additional, Hassall, Tim, additional, Anderson, Lisa K, additional, Bowman, Rayleen V, additional, Gattas, Michael, additional, Harris, Jessica E, additional, Marshall, Mhairi S, additional, Shaw, Janet G, additional, Wheeler, Lawrie, additional, Yang, Ian A, additional, Brown, Matthew A, additional, Fong, Kwun M, additional, Simpson, Fiona, additional, and Duncan, Emma L, additional

Published
2021
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35. A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young

Author

Graff, Sarah M., primary, Johnson, Stephanie R., additional, Leo, Paul J., additional, Dadi, Prasanna K., additional, Dickerson, Matthew T., additional, Nakhe, Arya Y., additional, McInerney-Leo, Aideen M., additional, Marshall, Mhairi, additional, Zaborska, Karolina E., additional, Schaub, Charles M., additional, Brown, Matthew A., additional, Jacobson, David A., additional, and Duncan, Emma L., additional

Published
2021
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37. Germline ERBB3 mutation in familial non-small-cell lung carcinoma : Expanding ErbB's role in oncogenesis

Author

McInerney-Leo, Aideen M., Chew, Hui Yi, Inglis, Po Ling, Leo, Paul J., Joseph, Shannon R., Cooper, Caroline L., Okano, Satomi, Hassall, Tim, Anderson, Lisa K., Bowman, Rayleen V., Gattas, Michael, Harris, Jessica E., Marshall, Mhairi S., Shaw, Janet G., Wheeler, Lawrie, Yang, Ian A., Brown, Matthew A., Fong, Kwun M., Simpson, Fiona, Duncan, Emma L., McInerney-Leo, Aideen M., Chew, Hui Yi, Inglis, Po Ling, Leo, Paul J., Joseph, Shannon R., Cooper, Caroline L., Okano, Satomi, Hassall, Tim, Anderson, Lisa K., Bowman, Rayleen V., Gattas, Michael, Harris, Jessica E., Marshall, Mhairi S., Shaw, Janet G., Wheeler, Lawrie, Yang, Ian A., Brown, Matthew A., Fong, Kwun M., Simpson, Fiona, and Duncan, Emma L.

Abstract

Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable, with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and subcellular localization were assessed, and cellular proliferation, pAkt/Akt and pERK levels determined. A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80 kDa form (which enhances proliferation) compared with the full-length (180 kDa) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localization pre-and post-epidermal growth factor stimulation; however, epidermal growth factor receptor (EGFR) levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared with wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 min post-stimulation compared with wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in onc

Published
2021

38. Multiple Endocrine Tumors Associated with Germline MAX Mutations : Multiple Endocrine Neoplasia Type 5?

Author

Seabrook, Amanda J., Harris, Jessica E., Velosa, Sofia B., Kim, Edward, McInerney-Leo, Aideen M., Dwight, Trisha, Hockings, Jason I., Hockings, Nicholas G., Kirk, Judy, Leo, Paul J., Love, Amanda J., Luxford, Catherine, Marshall, Mhairi, Mete, Ozgur, Pennisi, David J., Brown, Matthew A., Gill, Anthony J., Hockings, Gregory I., Clifton-Bligh, Roderick J., Duncan, Emma L., Seabrook, Amanda J., Harris, Jessica E., Velosa, Sofia B., Kim, Edward, McInerney-Leo, Aideen M., Dwight, Trisha, Hockings, Jason I., Hockings, Nicholas G., Kirk, Judy, Leo, Paul J., Love, Amanda J., Luxford, Catherine, Marshall, Mhairi, Mete, Ozgur, Pennisi, David J., Brown, Matthew A., Gill, Anthony J., Hockings, Gregory I., Clifton-Bligh, Roderick J., and Duncan, Emma L.

Abstract

Context: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. Objective: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. Methods: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. Results: Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8∗) was identified. Conclusion: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

Published
2021

39. Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals

Author

Bakshi, Andrew, Yan, Mabel, Riaz, Moeen, Polekhina, Galina, Orchard, Suzanne G., Tiller, Jane, Wolfe, Rory, Joshi, Amit, Cao, Yin, McInerney-Leo, Aideen M., Yanes, Tatiane, Janda, Monika, Soyer, H. Peter, Cust, Anne E., Law, Matthew H., Gibbs, Peter, McLean, Catriona, Chan, Andrew T., McNeil, John J., Mar, Victoria J., Lacaze, Paul, Bakshi, Andrew, Yan, Mabel, Riaz, Moeen, Polekhina, Galina, Orchard, Suzanne G., Tiller, Jane, Wolfe, Rory, Joshi, Amit, Cao, Yin, McInerney-Leo, Aideen M., Yanes, Tatiane, Janda, Monika, Soyer, H. Peter, Cust, Anne E., Law, Matthew H., Gibbs, Peter, McLean, Catriona, Chan, Andrew T., McNeil, John J., Mar, Victoria J., and Lacaze, Paul

Abstract

Background: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest. Methods: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma. Results: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma. Conclusions: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance.

Published
2021

40. Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals

Author

Bakshi, Andrew, primary, Yan, Mabel, additional, Riaz, Moeen, additional, Polekhina, Galina, additional, Orchard, Suzanne G, additional, Tiller, Jane, additional, Wolfe, Rory, additional, Joshi, Amit, additional, Cao, Yin, additional, McInerney-Leo, Aideen M, additional, Yanes, Tatiane, additional, Janda, Monika, additional, Soyer, H Peter, additional, Cust, Anne E, additional, Law, Matthew H, additional, Gibbs, Peter, additional, McLean, Catriona, additional, Chan, Andrew T, additional, McNeil, John J, additional, Mar, Victoria J, additional, and Lacaze, Paul, additional

Published
2021
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44. The impact of Marfan syndrome on an Aboriginal Australian family: 'I don't like it as much as I don't like cancer'.

Author

McInerney‐Leo, Aideen M., West, Jennifer, Meiser, Bettina, West, Malcolm, Toombs, Maree R., Brown, Matthew A., and Duncan, Emma L.

Abstract

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder. Aortic dilatation/dissection and ectopia lentis are the most severe features, which affect physical functioning and psychological well‐being. In Aboriginal Australians, there is little psychosocial research on genetic conditions. This study explored the physical, psychological, and practical impacts of MFS on Aboriginal Australians. Eighteen (8 affected and 10 unaffected) members of a large Aboriginal Australian family with MFS participated in an ethically approved study. Semi‐structured qualitative interviews were conducted, transcribed verbatim, and analyzed thematically. All individuals reported challenges from MFS, negatively affecting day‐to‐day living. Severe vision impairment was perceived as the greatest challenge, contributing to feelings of stigma and exclusion. With aging, concerns shifted toward cardiac complications. The unpredictability of lens dislocation and aortic dissection was reported to be psychologically challenging. Participants described MFS‐related barriers to obtaining and retaining employment, especially following cardiac surgery; with consequential psychological and financial hardships. Participants articulated that their cultural drive to support the ill and respectfully mourn the deceased, regardless of distance, resulted in a significant financial burden. Additionally, when hospitalization and/or funerals occurred, financially solvent individuals were expected to share resources, without any expectation of repayment or reciprocity (i.e., 'demand sharing', common in Aboriginal Australian culture). This study documents the nature and pervasiveness of uncertainty for both affected and unaffected members of an MFS family. Many reported challenges are consistent with other MFS cohorts (including stigma, social exclusion, and unemployment). However, our findings suggest that cultural values may exacerbate the financial costs of MFS for Aboriginal Australians. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

Author

Seabrook, Amanda J, primary, Harris, Jessica E, additional, Velosa, Sofia B, additional, Kim, Edward, additional, McInerney-Leo, Aideen M, additional, Dwight, Trisha, additional, Hockings, Jason I, additional, Hockings, Nicholas G, additional, Kirk, Judy, additional, Leo, Paul J, additional, Love, Amanda J, additional, Luxford, Catherine, additional, Marshall, Mhairi, additional, Mete, Ozgur, additional, Pennisi, David J, additional, Brown, Matthew A, additional, Gill, Anthony J, additional, Hockings, Gregory I, additional, Clifton-Bligh, Roderick J, additional, and Duncan, Emma L, additional

Published
2020
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48. Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

Author

Martin, Ella M M A, primary, Enriquez, Annabelle, additional, Sparrow, Duncan B, additional, Humphreys, David T, additional, McInerney-Leo, Aideen M, additional, Leo, Paul J, additional, Duncan, Emma L, additional, Iyer, Kavitha R, additional, Greasby, Joelene A, additional, Ip, Eddie, additional, Giannoulatou, Eleni, additional, Sheng, Delicia, additional, Wohler, Elizabeth, additional, Dimartino, Clémantine, additional, Amiel, Jeanne, additional, Capri, Yline, additional, Lehalle, Daphné, additional, Mory, Adi, additional, Wilnai, Yael, additional, Lebenthal, Yael, additional, Gharavi, Ali G, additional, Krzemień, Grażyna G, additional, Miklaszewska, Monika, additional, Steiner, Robert D, additional, Raggio, Cathy, additional, Blank, Robert, additional, Baris Feldman, Hagit, additional, Milo Rasouly, Hila, additional, Sobreira, Nara L M, additional, Jobling, Rebekah, additional, Gordon, Christopher T, additional, Giampietro, Philip F, additional, Dunwoodie, Sally L, additional, and Chapman, Gavin, additional

Published
2020
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50. Queensland Consumers’ Awareness and Understanding of Clinical Genetics Services

Author

Wallingford, Courtney K., primary, Cutler, Katrina, additional, Istiko, Satrio Nindyo, additional, Fowles, Lindsay F., additional, Lamb, Rachel, additional, Bean, Jessica, additional, Healy, Louise, additional, Hondow, Gary, additional, Pratt, Gregory, additional, Vidgen, Miranda E., additional, Waddell, Nicola, additional, Evans, Erin, additional, Bunker, David, additional, and McInerney-Leo, Aideen M., additional

Published
2020
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