Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging in patients with transient ischaemic attack and minor stroke : a systematic review, meta-analysis and economic evaluation

Erratum issued September 2015 Erratum DOI: 10.3310/hta18270-c201509Peer reviewedPublisher PD

Analysis of EEG patterns and genotypes in patients with Angelman syndrome.

We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006-2010), 115 had complete data (58 boys, median age 3.6 years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in50% theta and normal posterior rhythm; atypical deletions in patients with \u3e50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate