Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective.

Introduction: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH.

Main Recommendations: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH.

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics.

Moderation of baclofen response by a GABA receptor polymorphism: results from the BacALD randomized controlled trial.

Background And Aims: Baclofen has been shown to reduce alcohol consumption in alcohol-dependent individuals, but there is marked heterogeneity in response. An association between GABBR1 rs29220 and alcohol dependence has been demonstrated previously. The present study evaluated whether the response to baclofen is moderated by a single nucleotide polymorphism (rs29220) in the GABAB receptor subunit 1 gene (GABBR1).

The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6.

Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. A long-standing open question is why the same causal porphyria mutations exhibit widely variable penetrance and expressivity in different individuals. Here we show that severely affected porphyria patients harbour variant alleles in the ABCB6 gene, also known as Lan, which encodes an ATP-binding cassette (ABC) transporter.

Somatic DNA mutation analysis in targeted therapy of solid tumours.

Cancer is a disease of the genome with diverse aetiologies including the accumulation of acquired mutations throughout the genome. There has been a flood of knowledge improving our understanding of the biology and molecular genetics of melanoma, lung and colorectal cancer since the genomics era started. Translation of this knowledge into a better understanding of cell proliferation, survival and apoptosis has produced a paradigm shift in medical oncology enabling gene-based cancer treatment (called personalised or precision medicine).

Diagnostic validation of a familial hypercholesterolaemia cohort provides a model for using targeted next generation DNA sequencing in the clinical setting.

Our aim was to assess the sensitivity and specificity of a next generation DNA sequencing (NGS) platform using a capture based DNA library preparation method. Data and experience gained from this diagnostic validation can be used to progress the applications of NGS in the wider molecular diagnostic setting. A technical cross-validation comparing the current molecular diagnostic gold standard methods of Sanger DNA sequencing and multiplex ligation-dependant probe amplification (MLPA) versus a customised capture based targeted re-sequencing method on a SOLiD 5500 sequencing platform was carried out using a cohort of 96 familial hypercholesterolaemia (FH) samples.

Can ALS-associated C9orf72 repeat expansions be diagnosed on a blood DNA test alone?

Gene mutations that preferentially affect the CNS have been implicated in a number of neurological disorders. This leads to the possibility that a disease-causing mutation present only in CNS tissues could be missed if it were tested in a blood DNA sample only. The commonest mutation in amyotrophic lateral sclerosis (ALS) is an expansion of the hexanucleotide repeats of C9orf72.

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis.

Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care.

Understanding human genetic variation and how it impacts on gene function is a major focus in genomic-based research. Translation of this knowledge into clinical care is exemplified by pharmacogenetics/pharmacogenomics. The identification of particular gene variants that might influence drug uptake, metabolism, distribution or excretion promises a more effective personalised medicine approach in choosing the right drug or its dose for any particular individual.

Patterns of DNA mutations and ALK rearrangement in resected node negative lung adenocarcinoma.

Background: Many studies have examined specific mutations in patients with resected lung adenocarcinoma across heterogeneous stages, comprising predominantly advanced/metastatic disease, but there is little data regarding the mutation profile of patients with early stage node negative disease. The aim of this study was to identify patterns of mutations in early stage node negative lung adenocarcinoma.

Methods: A total of 204 patients who underwent resection for stage IB (sixth Ed American Joint Committee on Cancer) lung adenocarcinoma and received no neoadjuvant or adjuvant treatments were identified.

TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3' untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations.

Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study.

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.

Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region.

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.

Demographic history of Oceania inferred from genome-wide data.

Background: The human history of Oceania comprises two extremes: the initial colonizations of Near Oceania, one of the oldest out-of-Africa migrations, and of Remote Oceania, the most recent expansion into unoccupied territories. Genetic studies, mostly using uniparentally inherited DNA, have shed some light on human origins in Oceania, particularly indicating that Polynesians are of mixed East Asian and Near Oceanian ancestry. Here, we use ∼1 million single nucleotide polymorphisms (SNPs) to investigate the demographic history of Oceania in a more detailed manner.

DHPLC can be used to detect low-level mutations in amyotrophic lateral sclerosis.

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.

Pathology practice and pharmacogenomics.

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.

A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis.

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.

The future of genetic research in exercise science and sports medicine.

Background/aims: Genetic research is used to identify the relative contributions made by inherent abilities (nature) versus environmental effects (nurture) in human performance. The same approach allows a better understanding of how injuries or illnesses can result from sport or physical activity. Having identified the genes involved in athletic performance, there are the intriguing possibilities of using this information for talent search, developing individualized training programs and prevention of sports-related injuries.

Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis.

All patients with sporadic amyotrophic lateral sclerosis (SALS) have TDP-43 inclusions in their motor neurons, suggesting this protein plays a major role in the disease. Coding mutations in the gene for TDP-43, TARDBP, have been found in only a few patients with SALS. However, the non-coding regulatory regions of TARDBP have not yet been examined in SALS.

An analysis of the entire SOD1 gene in sporadic ALS.

Mutations in the superoxide dismutase 1 gene (SOD1) are associated with familial ALS but the role of SOD1 in sporadic ALS (SALS) is unclear. We therefore sequenced the entire SOD1 gene in 23 patients with SALS. DNA was extracted from frozen pre-frontal cerebral cortex and from blood.