Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.

The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

What is the Pathogenic CAG Expansion Length in Huntington's Disease?

Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds- the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70- 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60- 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.

The impact of endograft surveillance on a vascular imaging service.

BACKGROUND: Surveillance is considered mandatory after endovascular repair (EVR), but its impact on imaging services remains unreported. This study reports the effect of EVR surveillance on imaging resources. METHODS: A single-center's duplex database was interrogated from January 1, 2004 to January 1, 2012. All examinations requested by a vascular surgeon were reported, including preoperative abdominal aortic aneurysms, surveillance after EVR, lower limb arterial and venous duplex, and arteriovenous fistulae. RESULTS: A total of 24 309 patients underwent duplex. The EVR surveillance increased from 192 scans in 2004 to 1325 scans in 2011, 9.5% (192 of 2030) and 34.4% (1325 of 3850) of each year's examinations. By 2011, EVR surveillance was the most common indication for duplex. CONCLUSION: Lifelong EVR surveillance creates a rapidly increasing workload for imaging services. Further research should aim to reduce the burden of EVR surveillance. Targeting surveillance to the minority of patients at greatest risk of endograft failure might optimize the usage of imaging resources.