Idiopathic neonatal arterial ischaemic stroke: a trio-based whole-exome sequencing study.
OBJECTIVE: To assess the contribution of rare coding genetic variants to idiopathic neonatal arterial ischaemic stroke (NAIS). DESIGN: Observational genetic study using trio-based whole-exome sequencing (WES). SETTING: Multicentre study. PATIENTS: 23 newborns diagnosed with idiopathic NAIS and their biological parents. INTERVENTIONS: WES-trio with a customised workflow for filtering and interpreting variants in de novo autosomal dominant and recessive inheritance models. MAIN OUTCOME MEASURES: Identification of pathogenic (P) or likely pathogenic (LP) variants potentially associated with NAIS. RESULTS: We identified 28 unique rare de novo variants in 28 genes across 23 newborns with NAIS. Under the autosomal recessive model, no candidate genes were identified. No common P/LP variant across the 23 newborns was detected. In-silico predictors and comprehensive knowledge-driven analysis highlighted PIK3CD (p.Gln431Arg) as a candidate gene in one patient with perforant stroke. However, no more cases were identified with PIK3CD variants, and functional studies are warranted to assess its pathogenicity impact. CONCLUSIONS: Trio-based WES did not identify a monogenic cause for idiopathic NAIS. Coding variants therefore appear unlikely to explain the underlying genetic base of the disease. Furthermore, PIK3CD (p.Gln431Arg) may contribute to perforant stroke, although it requires further association evidence. As the potential role of non-coding or structural variants in NAIS remains possible, genome-wide long-read sequencing approaches may provide further insights into the genetic architecture of this condition.