Our data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification. Ann Neurol 2016;79:991-999.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

The Canada Excellence Research Chairs (CERC), Leading Edge Endowment Fund (LEEF), Don Rix BC Leadership Chair in Genetic Medicine, National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Michael J Fox Foundation, Mayo Foundation, the Roger de Spoelberch Foundation, and GlaxoSmithKline.

Background & Aims: Despite the high burden of hepatitis C virus (HCV) infection among people who inject drugs (PWID), uptake of interferon-based therapies has been extremely low. Increasing availability of direct-acting antiviral (DAA)-based therapies offers the possibility of rapid treatment expansion with the goal of controlling the HCV epidemic. We evaluated DAA-based treatment uptake among HCVpositive PWID in Vancouver after introduction of DAAs in the government drug formulary. Methods: Using data from three cohorts of PWID in Vancouver, Canada, we investigated factors associated with DAA-therapies uptake among participants with HCV Results: Of the 915 HCV-positive PWID, 611 (66.8%) were recent PWID and 369 (40.3%) had HIV coinfection. During the study period, 146 (16.0%) initiated DAA-therapies, a rate of 6.0 per 100 person-year, with higher initiation rates among non-recent PWID and an increasing trend over time. In multivariable analysis, HIV coinfection (Adjusted Odds Ratio [AOR] = 2.29, 95% Confidence Interval [CI]: 1.55-3.40), white race (AOR = 1.56, 95% CI: 1.05-2.35), and engagement in HCV care (AOR = 1.94, 95%CI: 1.31-2.90) were positively associated with DAA-therapies uptake, while high-risk drinking (AOR = 0.47, 95% CI: 0.23-0.88) and daily crack use were negatively associated (AOR = 0.41, 95% CI: 0.17-0.85). Among recent PWID, engagement in opioid agonist therapy emerged as an independent correlate of DAA uptake. Conclusions:Despite increases in HCV treatment uptake among PWID after the introduction of DAAs in our setting, disparities in access remain. Social-structural and behavioural barriers to HCV care should be addressed for the success of any HCV elimination strategy.

With one in five PWID being exposed to fentanyl, there is an urgent need to design and scale up interventions to reduce overdose risk, including a range of opioid agonist therapies.