Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM-CGG expansion of 55-199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

Investigation of current models of care for genetic heart disease in Australia: A national clinical audit.

BACKGROUND: This sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac genetics clinics. METHOD: An audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test. RESULTS: This audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease. CONCLUSION: We provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape.

Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells.

Mucopolysaccharidoses (MPS) are inherited metabolic disorders that arise from a complete loss or a reduction in one of eleven specific lysosomal enzymes. MPS children display pathology in multiple cell types leading to tissue and organ failure and early death. Mesenchymal stem cells (MSCs) give rise to many of the cell types affected in MPS, including those that are refractory to current treatment protocols such as hematopoietic stem cell (HSC) based therapy. In this study we compared multiple MPS enzyme production by bone marrow derived (hBM) and dental pulp derived (hDP) MSCs to enzyme production by HSCs. hBM MSCs produce significantly higher levels of MPS I, II, IIIA, IVA, VI and VII enzyme than HSCs, while hDP MSCs produce significantly higher levels of MPS I, IIIA, IVA, VI and VII enzymes. Higher transfection efficiency was observed in MSCs (89%) compared to HSCs (23%) using a lentiviral vector. Over-expression of four different lysosomal enzymes resulted in up to 9303-fold and up to 5559-fold greater levels in MSC cell layer and media respectively. Stable, persistent transduction of MSCs and sustained over-expression of MPS VII enzyme was observed in vitro. Transduction of MSCs did not affect the ability of the cells to differentiate down osteogenic, adipogenic or chondrogenic lineages, but did partially delay differentiation down the non-mesodermal neurogenic lineage.