Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum

OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes. METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS. RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31/114 gene-disease relationships curated (27%); moderate for 38 (33%); limited for 43 (38%); and 2 as disputed (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 autosomal dominant, and 3 X-linked. INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multi-system organ surveillance, recurrence risk counselling, reproductive choice, natural history studies and eligibility for interventional clinical trials. This article is protected by copyright. All rights reserved

Replication data for: The Consequences of Partisanship in Economic Perceptions

Data and materials to replicate all analyses in "The Consequences of Partisanship in Economic Perceptions.

The impact of patient education on the quality of inpatient bowel preparation for colonoscopy

BACKGROUND: For patients requiring colonoscopy while admitted to hospital, achieving adequate cleansing of the colon is often difficult

O sweet spot where art thou? Light treatment of Seasonal Affective Disorder and the circadian time of sleep

This study investigated Lewy's Phase Shift Hypothesis (PSH) for winter Seasonal Affective Disorder, which asserts that the phase angle difference (PAD) between circadian and sleep rhythms is critical in the mechanism of light's therapeutic action. Specifically, we sought to test whether a euthymic 'sweet spot' could be identified at a PAD (between temperature minimum and wake time) of circa 3 h. After a baseline week, symptomatic SAD patients (N = 43) received 8 weeks of morning light treatment. Analyses were based on SIGH-SAD ratings made at baseline and posttreatment. Also estimated pre- and posttreatment were Tmin (calculated from an algorithm based on Morningness-Eveningness self-report scores), and the phase of the sleep-wake rhythm (as assessed by daily sleep logs). It was predicted that a quadratic relationship would exist between PAD and depression ratings at baseline and posttreatment, with lowest levels around PAD = 3 h. It was further predicted that shift towards PAD = 3 h with treatment would be associated with decreases in depression with treatment. Although trends were in the expected direction, none of the three predictions were supported. Findings are discussed in terms of the study's limitations and the experimental challenge of parsing independent and interacting contributions of sleep and circadian phase