Genomic analysis of presumed perinatal stroke in Saudi Arabia reveals a strong monogenic contribution

• Published in: Human genetics Vol. 143; no. 1; pp. 59 - 69
• Main Authors: Alshammari, Muneera J., Shamseldin, Hanan E., Essbaiheen, Fahad, Eltahir, Sara H., Alruwaili, Ashwag R., Abdulwahab, Firdous, Alkuraya, Fowzan S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2024; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cerebral infarction; Developmental disabilities; Gene Function; Genomic analysis; Human Genetics; Metabolic Diseases; Molecular Medicine; Morbidity; Neonates; Neuroimaging; Original Investigation; Risk factors; Seizures; Stroke
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-023-02621-6

Perinatal stroke is associated with significant short- and long-term morbidity and has been recognized as the most common cause of cerebral palsy in term infants. The diagnosis of presumed perinatal stroke (PPS) is made in children who present with neurological deficit and/or seizures attributable to focal chronic infarction on neuroimaging and have uneventful neonatal history. The underlying mechanism of presumed perinatal stroke remains unknown and thorough investigation of potential monogenic causes has not been conducted to date. Here, we describe the use of untargeted exome sequencing to investigate a cohort of eight patients from six families with PPS. A likely deleterious variant was identified in four families. These include the well-established risk genes
COL4A2
and
JAM3
. In addition, we report the first independent confirmation of the recently described link between
ESAM
and perinatal stroke. Our data also highlight
NID1
as a candidate gene for the condition. This study suggests that monogenic disorders are important contributors to the pathogenesis of PPS and should be investigated by untargeted sequencing especially when traditional risk factors are excluded.