Genomic analysis of presumed perinatal stroke in Saudi Arabia reveals a strong monogenic contribution
Muneera J Alshammari1, Hanan E Shamseldin2, Fahad Essbaiheen3
1Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
Insights
Monogenic disorders, or inherited conditions, are significant contributors to presumed perinatal stroke (PPS). Untargeted exome sequencing identified genetic variants in families with PPS, suggesting a role for these conditions.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Perinatal stroke (PS) is a leading cause of cerebral palsy in term infants.
- Presumed perinatal stroke (PPS) is diagnosed in infants with neurological deficits and imaging evidence of stroke, despite a normal neonatal history.
- The genetic underpinnings of PPS remain largely unexplored.
Purpose of the Study:
- To investigate the potential role of monogenic disorders in presumed perinatal stroke (PPS).
- To identify genetic variants associated with PPS using untargeted exome sequencing.
Main Methods:
- Untargeted exome sequencing was performed on a cohort of eight patients from six families with PPS.
- Analysis focused on identifying likely deleterious variants in known and novel candidate genes.
Main Results:
- A likely deleterious variant was identified in four of the six families studied.
- Confirmed known risk genes (COL4A2, JAM3) and provided independent confirmation for ESAM.
- Highlighted NID1 as a novel candidate gene for PPS.
Conclusions:
- Monogenic disorders are significant contributors to the pathogenesis of presumed perinatal stroke.
- Untargeted exome sequencing is a valuable tool for investigating PPS, particularly when conventional risk factors are absent.
Abstract:
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.
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