%0 Journal Article %~ PubMed %A Lee, J-M %A Ramos, E M %A Lee, J-H %A Gillis, T %A Mysore, J S %A Hayden, M R %A Warby, S C %A Morrison, P %A Nance, M %A Ross, C A %A Margolis, R L %A Squitieri, F %A Orobello, S %A Di Donato, S %A Gomez-Tortosa, E %A Ayuso, C %A Suchowersky, O %A Trent, R J A %A McCusker, E %A Novelletto, A %A Frontali, M %A Jones, R %A Ashizawa, T %A Frank, S %A Saint-Hilaire, M H %A Hersch, S M %A Rosas, H D %A Lucente, D %A Harrison, M B %A Zanko, A %A Abramson, R K %A Marder, K %A Sequeiros, J %A Paulsen, J S %A , PREDICT-HD study of the Huntington Study Group (HSG) %A Landwehrmeyer, G B %A , REGISTRY study of the European Huntington's Disease Network %A Myers, R H %A , HD-MAPS Study Group %A MacDonald, M E %A Gusella, J F %A , COHORT study of the HSG %T CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. %B Neurology %D 2012 %C United States %I Lippincott Williams & Wilkins %V 78 %N 10 %P 690-695 %@ 1526-632X %X Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Lee, Jong-Min %A Gillis, Tammy %A Mysore, Jayalakshmi Srinidhi %A Ramos, Eliana Marisa %A Myers, Richard H %A Hayden, Michael R %A Morrison, Patrick J %A Nance, Martha %A Ross, Christopher A %A Margolis, Russell L %A Squitieri, Ferdinando %A Griguoli, Annamaria %A Di Donato, Stefano %A Gomez-Tortosa, Estrella %A Ayuso, Carmen %A Suchowersky, Oksana %A Trent, Ronald J %A McCusker, Elizabeth %A Novelletto, Andrea %A Frontali, Marina %A Jones, Randi %A Ashizawa, Tetsuo %A Frank, Samuel %A Saint-Hilaire, Marie-Helene %A Hersch, Steven M %A Rosas, Herminia D %A Lucente, Diane %A Harrison, Madaline B %A Zanko, Andrea %A Abramson, Ruth K %A Marder, Karen %A Sequeiros, Jorge %A MacDonald, Marcy E %A Gusella, James F %T Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. %B American Journal of Human Genetics %D 2012 %C United States %I Cell Press %V 90 %N 3 %P 434-444 %@ 0002-9297 %X Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ?50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ?83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Poursoltan, Pirooz %A Currey, Nicola %A Pangon, Laurent %A van Kralingen, Christa %A Selinger, Christina I %A Mahar, Annabelle %A Cooper, Wendy A %A Kennedy, Catherine W %A McCaughan, Brian C %A Trent, Ronald %A Kohonen-Corish, Maija R J %T Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer. %B Lung Cancer %D 2012 %C Ireland %I Elsevier Ireland Ltd %V 77 %N 2 %P 272-276 %@ 1872-8332 %X ''Mutated in Colorectal Cancer'' (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41-49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms. %Z FOR Codes: 1112 %0 Journal Article %~ PubMed %A Ramos, Eliana Marisa %A Latourelle, Jeanne C %A Lee, Ji-Hyun %A Gillis, Tammy %A Mysore, Jayalakshmi S %A Squitieri, Ferdinando %A Di Pardo, Alba %A Di Donato, Stefano %A Hayden, Michael R %A Morrison, Patrick J %A Nance, Martha %A Ross, Christopher A %A Margolis, Russell L %A Gomez-Tortosa, Estrella %A Ayuso, Carmen %A Suchowersky, Oksana %A Trent, Ronald J %A McCusker, Elizabeth %A Novelletto, Andrea %A Frontali, Marina %A Jones, Randi %A Ashizawa, Tetsuo %A Frank, Samuel %A Saint-Hilaire, Marie-Helene %A Hersch, Steven M %A Rosas, Herminia D %A Lucente, Diane %A Harrison, Madaline B %A Zanko, Andrea %A Marder, Karen %A Gusella, James F %A Lee, Jong-Min %A Alonso, Isabel %A Sequeiros, Jorge %A Myers, Richard H %A Macdonald, Marcy E %T Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset. %B Human Genetics %D 2012 %C Germany %I Springer %V 131 %N 12 %P 1833-1840 %@ 0340-6717 %X %Z FOR Codes: 604 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Cheong, Pak Leng %A Trent, Ronald J %A Yu, Bing %T Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. %B Neuroreport %D 2012 %C United States %I Lippincott Williams & Wilkins %V 23 %N 9 %P 556-559 %@ 0959-4965 %X Abnormally expanded C9orf72 hexanucleotide repeats are found in up to 7% of patients with sporadic amyotrophic lateral sclerosis (SALS). It is not known whether the sporadic nature of the disease represents incomplete penetrance of the phenotype or expansion of the repeat in the SALS patient. The sizes of C9orf72 hexanucleotide repeats were measured in blood DNA of 43 SALS patients and their parents who had no symptoms of ALS. Two SALS patients (4.7%) had abnormally expanded (>30 repeats) C9orf72 repeats. Both of their fathers (one with dementia) also had abnormally expanded repeats. Nine SALS patients had intermediate-normal repeat sizes (7-30 repeats); in each of these, one parent had a similar repeat size. In the remaining 32 SALS patients, the repeat sizes were low-normal (<7 repeats). There was no evidence of repeat instability leading to abnormal numbers of repeats in any SALS patient in this trio cohort. Our results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related SALS. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Watts, Gerald F %A Sullivan, David R %A Poplawski, Nicola %A van Bockxmeer, Frank %A Hamilton-Craig, Ian %A Clifton, Peter M %A O'Brien, Richard %A Bishop, Warrick %A George, Peter %A Barter, Phillip J %A Bates, Timothy %A Burnett, John R %A Coakley, John %A Davidson, Patricia %A Emery, Jon %A Martin, Andrew %A Farid, Waleed %A Freeman, Lucinda %A Geelhoed, Elizabeth %A Juniper, Amanda %A Kidd, Alexa %A Kostner, Karam %A Krass, Ines %A Livingston, Michael %A Maxwell, Suzy %A O'Leary, Peter %A Owaimrin, Amal %A Redgrave, Trevor G %A Reid, Nicola %A Southwell, Lynda %A Suthers, Graeme %A Tonkin, Andrew %A Towler, Simon %A Trent, Ronald %A , Familial Hypercholesterolaemia Australasia Network Consensus Group (Australian Atherosclerosis Society) %T Familial hypercholesterolaemia: A model of care for Australasia. %B Atherosclerosis. Supplements %D 2011 %C Ireland %I Elsevier Ireland Ltd %V 12 %N 2 %P 221¿263 %@ 1878-5050 %X Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification. %Z FOR Codes: 110299 %0 Journal Article %~ PubMed %A Luquin, Natasha %A Yu, Bing %A Trent, Ronald J %A Pamphlett, Roger %T DHPLC can be used to detect low-level mutations in amyotrophic lateral sclerosis. %B Amyotrophic Lateral Sclerosis %D 2010 %C United Kingdom %I Informa Healthcare %V 11 %N 1-2 %P 76-82 %@ 1471-180X %X Somatic mutations have been suggested as a cause of sporadic amyotrophic lateral sclerosis (SALS). These mutations can be difficult to detect since they may involve only a small percentage of cells within the tissue, so we devised a method to detect low mutation levels in brain DNA. Different proportions of a known SOD1 mutation were prepared to determine the sensitivity of DHPLC. The fraction containing the mutant signal was collected and re-amplified (''enriched'') to increase sensitivity and to dideoxy sequence the mutation. The combined technique was used to screen all exons and the promoter of SOD1 in 23 SALS brains. DHPLC could detect a known SOD1 mutation in 5% of a sample of brain tissue. Using our enrichment technique doubled the height of the mutant sequencing signal, which allowed identification of an unknown mutation in 10% of brain tissue. No SOD1 mutations were found in the SALS brains using this technique. In conclusion, combining DHPLC and sequencing doubles the sensitivity of sequencing alone and can detect low levels of known and unknown mutations in brain DNA. No SALS SOD1 somatic mutations were detected, but DHPLC would be useful in looking for somatic mutations in other SALS candidate genes. %Z FOR Codes: 60408 %0 Journal Article %~ Isi %A Wollstein, A. %A Lao, O. %A Becker, C. %A Brauer, S. %A Trent, R. J. %A Nurnberg, P. %A Stoneking, M. %A Kayser, M. %T Demographic History of Oceania Inferred from Genome-wide Data %B Current Biology %D 2010 %C United States %I Cell Press %V 20 %N 22 %P 1983-1992 %@ 0960-9822 %X %Z FOR Codes: 60401 %0 Book Section %A Yu, Bing %A Trent, Ronald %T Genetics of Athletic Performance. %B Encyclopedia of Life Sciences %D 2010 %C United Kingdom %I John Wiley & Sons Ltd. %V %N %P 1-8 %@ 9780470664780 %X %Z FOR Codes: 60403 %0 Journal Article %~ PubMed %A Trent, Ronald Ja %T Pathology practice and pharmacogenomics. %B Pharmacogenomics %D 2010 %C United Kingdom %I Future Medicine Ltd. %V 11 %N 1 %P 105-111 %@ 1744-8042 %X New technologies emerging from the Human Genome Project and the rapidly expanding direct-to-consumer DNA testing have provided a challenging environment for the entry of pharmacogenomics into clinical practice. The traditional pathology laboratory, which is centered around a referring clinician and the patient, is also being reshaped by these developments. These changes are occurring as the shrinking health dollar imposes a greater focus on preventative medicine. For the latter to benefit from genomics requires the community to be engaged, and the development of the disease process identified earlier than otherwise possible. These two prerequisites are now being sought through the concept of ''personalized medicine''. Much has been occurring in a relatively short time frame, and as a consequence, education becomes a major rate-limiting step to change. %Z FOR Codes: 60408 %0 Journal Article %~ PubMed %A Morahan, Julia M %A Yu, Bing %A Trent, Ronald J %A Pamphlett, Roger %T A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis. %B Amyotrophic lateral sclerosis %D 2009 %C United Kingdom %I Informa %V 10 %N 5-6 %P 418-429 %@ 1471-180X %X Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p