To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy.
Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells.
Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 ( AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations.
We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.
(1) Non-profit entity: Therapeutic Advisory Committee, Treat-NMD (2) commercial entity: Data safety monitoring board for Eli-Lilly pharmaceuticals
(1) Associate Editor, Journal of Pediatric Neurology 2007- 2) Editorial Board, Journal of Clinical Neuroscience 2009
Darras BT, Jones HR Jr, Ryan MM, De Vivo DC (editors). Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician's Approach. 2nd edition. San Diego: Academic Press, 2015.
National Health and Medical Research Council Centre for Research Excellence Grant I.D. 1031893.
Cancer Council Australia Grant 1006349 Chief Investigator (2011-2014) NHMRC Project Grant 1041860 Chief Investigator (2013-2015) NHMRC Project Grant 1049299 Chief Investigator (2013-2015) NHMRC Project Grant 1059993 Chief Investigator (2014-15) NHMRC Project Grant 1059666 Chief Investigator (2014-2016)
Cancer Australia & Prostate Cancer Foundation of Australia APP1059423 Chief Investigator (2014-16)
Simons Foundation CURE Foundation John and Marsha Goldman Foundation
Law Firms: Sheuerman, Martini & Tabari; Galloway and Lucchese; Zuger, Kirmis & Smith; Donahoe & Kearney; LaFollette, Johnson; Huff, Powell & Bailey; Bell, Roper and Kohlmyer.
Macular Telangiectasia (MacTel) Consortium Scientific advisor March 2012 (non-profit) Department of Health (Australian Government), scientific advisory member (non-profit)
Conference Presentations 2012 The 7th International Conference on Genomics & Bio- IT APAC 2012, Hong Kong, China (Invited Speaker) International Mathematics Institute conference, Pacific Region, Tsukuba, Japan (Invited Speaker) Australian Statistical Society Conference, Adelaide (Invited speaker) International Stroke Genetics Meeting, Newcastle, Australia (Plenary speaker, all expenses paid) Human Genome Meeting, Sydney (Invited Speaker) Other Presentations Discussant & Scientific advisor, MacTel Consortium Meeting, Los Angeles, USA (Invited, all expenses paid), March 2012
Associate Editor, Statistical Applications in Genetics and Molecular Biology, 2006-2012 F1000 Faculty Member Medical Genetics section 2011-present
Method of determining response to treatment with immunomodulatory composition Details genetic markers that predict response to Hepatitis C treatment. US provisional patent 150230, filed April 29th, 2011 (1407994)
Other Presentations Discussant & Scientific advisor, MacTel Consortium Meeting, Los Angeles, USA (Invited, all expenses paid), March 2012 2014 Human Genetics Society of Australia Conference, August, Adelaide, Australia (Plenary speaker, all expenses paid) Australian Statistical Society-Institute of Mathematical Statistics, July, Sydney, Australia (Session Organiser, Invited Speaker, Registration paid) International Conference on Systems Biology, September, Melbourne (Invited Speaker, Registration and Accommodation paid) 2013 Sixth Barossa Meeting “Cell Signalling Cell Signalling in the Omics Era”, November, Barossa Valley, Australia, November (Invited Speaker, all expenses paid) The 8th International Conference on Genomics & Bio-IT APAC November, Shenzhen, China (Invited Speaker, all expenses paid except air travel)
2014-2018 NHMRC Program Grant Application APP1054618, Speed TP, Smyth GK, Bahlo M, Papenfuss TP, “Computational and statistical bioinformatics for medical ‘omics’” 2013-2015 NHMRC Project Grant Application APP1044175, Scheffer I, Lockhart P, Bahlo M, Delatycki M, Wilson S, “Genetics of Autism” 2013-2014 National Heart Foundation Award G 12S 6597, NHMRC Project Grant Application APP1051333 Fatkin D, Bahlo M, Kikuchi K, “Genes and atrial fibrillation” 2012-2014 Australian Research Council (ARC) Discovery Project Grant DP120100285. Scheffer IE, Morgan AT, Hildebrand MS, Connelly A, Liegeois F, Bahlo M, Smith RJ. “Elucidating the neural pathways and genetic basis of speech” 2011-2012 Victorian Life Sciences Computing Initiative (VLSCI) half-stipend for UROP student David Wakeham, Bahlo M, “Analysis of massively parallel sequencing data in family studies”, 2010-2012 Royal Melbourne Hospital Home Lottery Research Awards “Genome-wide Multigenic Pharmacogenomic Classifiers for Newly Treated Epilepsy”, Petrovski S, O'Brien TJ, Huggins RM., Moldovan M, Bahlo M 2010-2013 Leukemia Foundation National Research Program. Fuller SJ, Hahn CN, Bahlo M, Scott HS, Wiley JS. “Using familial predisposition to Chronic Lymphocytic Leukaemia to follow disease progression” 2010-2014 ARC Future Fellowship, Level 1, ID # FT100100764, “Developing methods for the analysis of massively parallel sequencing data in family studies” 2011-2015 NHMRC Senior Research Fellowship A, ID #1002098, “Using modern DNA techniques to identify the causes of genetic disease in families” (This has been accepted as an honorary appointment) Program Grant Program Grant ID # 490037, Foote SJ, Speed TP, Smyth GK, Bahlo M, Chalmers D, Amor DJ, “Genetic and Bioinformatic Analysis of Complex Human Diseases”, 2011 Cancer Australia Foote SJ, Dickinson J, Stankovich J, Thomson R, Bahlo M “Integrative genomic approaches to understanding the genetics of prostate cancer” 2009-2011 ARC Linkage Grant LPO990067 “Functional Genomics to Predict and Enhance Response to Interferon” George J, Booth D, Yang J, Bahlo M. 2007-2011 DEST International Science Linkages grant ID # CG120047. Berkovic S, Korczyn M, Mulley J, Gecz J, Bahlo M. “An international strategy for gene identification leading to discovery of new targets for treatment of neurological disease.”
Human Genetics Society of Australia Royal Statistical Society Institute of Mathematical Statistics Biometrics Society of Australasia Australian Statistics Society American Society of Human Genetics International Genetic Epidemiology Society
Honoraria to cover flights and accommodation to attend and lecture at the Asia Oceania Congress of Child Neurology, Taipei , May 2015.
2014- Chief Investigator (CIC), Using high-throughput genomics to reveal the deleterious genetic changes that underlie paediatric leukoencephalopathies. (National Health and Medical Research Council Project Grant 1068278). 2014- Chief investigator (CIB), Determining the genetic control of corpus callosum development. (National Health and Medical Research Council Project Grant 1059666).
(1) Genetics Research International, Editorial board member, 2010-2015 (2) Open Access (OA) Genetics, Editorial board member, 2012-2015
1. National Health and Medical Research Council (Australia) Project Grant APP1059666, Chief Investigator, 2014-2016. 2. National Health and Medical Research Council (Australia) Project Grant APP1041860, Chief Investigator, 2013-2015. 3. National Health and Medical Research Council (Australia) Project Grant APP1046206, Chief Investigator, 2013-2015. 4. National Health and Medical Research Council (Australia) Project Grant APP1044175, Chief Investigator, 2013-2015. 5. National Health and Medical Research Council (Australia) Career Development Fellowship Level 2, APP1032364 2012-2015.
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