{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Laboratory of Neurogenetics and Genomic Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain"
      ],
      "name": "Jonathan Olival"
    },
    {
      "affiliations": [
        "Laboratory of Neurogenetics and Genomic Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain",
        "Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain"
      ],
      "name": "Janet Hoenicka"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Department of Neonatology, Hospital Clínic (Maternitat)-IDIBAPS, Barcelona, Spain"
      ],
      "name": "Gemma Arca"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Neonatal Unit, Hospital Universitario de Burgos, Burgos, Spain"
      ],
      "name": "Juan Arnaez"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Neonatal Department, Hospital Sant Joan de Déu, Barcelona, Spain"
      ],
      "name": "Thais Agut"
    },
    {
      "affiliations": [
        "Laboratory of Neurogenetics and Genomic Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain",
        "Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain"
      ],
      "name": "Joan Maynou"
    },
    {
      "affiliations": [
        "Neonatal Brain Research Group, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain",
        "Parc Sanitari Sant Joan de Déu, Barcelona, Spain"
      ],
      "name": "Christian Stephan-Otto"
    },
    {
      "affiliations": [
        "Neonatal Brain Research Group, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain",
        "Departament de Psiquiatria, Institut d’Investigació Biomèdica-Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain"
      ],
      "name": "Christian Núñez"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Departamento de Neonatología, Hospital Puerta del Mar, Cádiz, Spain"
      ],
      "name": "Isabel Benavente"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Departamento de Neonatología, Hospital Puerta del Mar, Cádiz, Spain"
      ],
      "name": "Simón Lubián-López"
    },
    {
      "affiliations": [
        "Laboratory of Neurogenetics and Genomic Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain",
        "Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain"
      ],
      "name": "Francesc Palau"
    },
    {
      "affiliations": [
        "Neonatal Neurology. NeNe Foundation, Madrid, Spain",
        "Iberoamerican Society of Neonatology (SIBEN), New Jersey, Northeastern United States, USA"
      ],
      "name": "Alfredo García-Alix"
    }
  ],
  "title": "Idiopathic neonatal arterial ischaemic stroke: a trio-based whole-exome sequencing study",
  "uid": "84c91892-7942-57dc-86b6-fc9d239394c4"
}