Stroke Study Reveals a High Frequency of Mendelian Disorders

The study covered in this summary was published in as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Exome sequencing (ES) is useful in evaluating stroke patients, particularly younger patients less than 1 year old.

  • Due to different etiologies of stroke, patients are more likely to benefit from a broad array of genetic tests.

Why This Matters

  • Stroke is a leading cause of death and disability worldwide.

  • Though rare in children, pediatric strokes often occur as part of an inherited genetic disorder.

  • A previous study successfully diagnosed 10% of pediatric strokes attributed to Mendelian causes using genetic studies.

Study Design

  • The study was retrospective and occurred between June 2012 and May 2021.

  • A total of 124 patients between the ages of 10 days and 69 years with a personal history of stroke or cerebral infarcts were included.

  • Following informed consent, the patients underwent three types of ES: proband-only ES in 89 patients, trio ES in 19 patients, and critical-trio ES in 15 patients. One patient underwent all three assays.

  • All samples were analyzed by chromosomal microarrays for quality control.

  • Data were interpreted according to American College of Medical Genetics and Genomics guidelines.

  • Criteria for molecular diagnosis: detection of pathogenic or likely pathogenic variants in gene associated with reported phenotype submitted to the laboratory whose zygosity matched gene’s established pattern of inheritance.

Key Results

  • Out of the 124 patients sampled, there was a diagnostic rate of 19.4%, with 8.9% being fully diagnosed by meeting all three criteria for molecular diagnosis.

  • There were differences in diagnostic rate based on the age of patients with the highest diagnostic rate found in patients under age 1 year.

  • Diagnostic rate of critical-trio ES was highest with diagnoses such as Aicardi-Goutières syndrome and POLG-related syndromes.

  • There were no recurrent genes observed in fully diagnosed patients, but COL4A1 and ATP13A2 were recurrent genes observed in the “probably diagnosed” group.

  • Some fully diagnosed cases included disorders not previously associated with stroke, most notably Costello syndrome, Sotos syndrome, and autosomal recessive polycystic kidney disease.


  • Due to different etiologies of stroke, diagnosis and selection of patients for genetic analysis, especially younger patients, were difficult.

  • Though critical-trio ES had the highest diagnostic rate, the average age of patients who received trio studies was younger, that is, 27% of the sampled patients underwent trio studies, and of these, 58% were infants.

  • Patients are more likely to benefit from broad genetic testing due to findings of syndromes not previously associated with stroke.


  • Some authors received grants from the National Human Genome Research Institute for the study.

This is a summary of a preprint research study, “Clinical Exome Sequencing for Stroke Evaluation Uncovers a High Frequency of Mendelian Disorders: A Retrospective Study,” written by Runjun Kumar and colleagues from the Baylor College of Medicine, Houston, Texas, on medRxiv provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on

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