We present data on the known risk factors encountered in children presenting with a first arterial ischemic stroke to a single tertiary center over 22 years. Two hundred twelve patients (54% male; median age, 5 years) were identified. One hundred fifteen (54%) were previously healthy. Cerebral arterial imaging was undertaken in 185 patients (87%) and was abnormal in 79%. Of 104 previously healthy patients investigated with echocardiography, only 8 had abnormal studies. Genetic or acquired conditions causing thrombophilia were rare. Forty percent of patients were anemic, and 21% either had elevated total plasma homocysteine or were homozygous for the t-MTHFR mutation. Trauma and previous varicella zoster infection were significantly more common in the previously healthy group. There was a significant association between cerebral arterial abnormalities and systolic blood pressure greater than 90th percentile and a trend for an association with varicella within the previous year. Clinical history and examination usually identify underlying risk factors and precipitating triggers for arterial ischemic stroke in childhood. Cerebral arterial imaging is usually abnormal, but echocardiography and prothrombotic screening are commonly negative.

RFs, especially arteriopathy, are common in childhood AIS. Variations in RFs by age or geography may inform prioritization of investigations and targeted preventative strategies.

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Background The UK 100,000 Genomes Project is in the process of investigating the role of genome sequencing of patients with undiagnosed rare disease following usual care, and the alignment of research with healthcare implementation in the UK’s national health service. (Other parts of this Project focus on patients with cancer and infection.) Methods We enrolled participants, collected clinical features with human phenotype ontology terms, undertook genome sequencing and applied automated variant prioritization based on virtual gene panels (PanelApp) and phenotypes (Exomiser), alongside identification of novel pathogenic variants through research analysis. We report results on a pilot study of 4660 participants from 2183 families with 161 disorders covering a broad spectrum of rare disease. Results Diagnostic yields varied by family structure and were highest in trios and larger pedigrees. Likely monogenic disorders had much higher diagnostic yields (35%) with intellectual disability, hearing and vision disorders, achieving yields between 40 and 55%. Those with more complex etiologies had an overall 25% yield. Combining research and automated approaches was critical to 14% of diagnoses in which we found etiologic non-coding, structural and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohort-wide burden testing across 57,000 genomes enabled discovery of 3 new disease genes and 19 novel associations. Of the genetic diagnoses that we made, 24% had immediate ramifications for the clinical decision-making for the patient or their relatives. Conclusion Our pilot study of genome sequencing in a national health care system demonstrates diagnostic uplift across a range of rare diseases. (Funded by National Institute for Health Research and others)