Stroke is one of the most frequent causes of morbidity, occurring in approximately 8% of children with sickle cell disease during their first decade of life. Despite a single mutation responsible for sickle cell disease, substantial heterogeneity in the clinical severity of patients exists. The role of potential modifying genes on the clinical phenotype has not been fully explored.

To test whether there is a genetic component of stroke in children with sickle cell disease, we used a case control study design. A case was defined as a patient with sickle cell disease, a history of stroke and blood transfusion therapy for secondary prevention of stroke. A control was defined as a patient with sickle cell disease, no history of stroke, and a normal magnetic resonance image (MRI) of the brain. We compared the frequency of stroke in siblings and first cousins with sickle cell disease for both cases and controls.

In six Pediatric Hematology Centers encompassing over 1200 patients with sickle cell disease, we identified 60 family pedigrees of children with strokes and 50 families of children without overt or silent strokes. In both the cases and controls, we directly compared the frequency of strokes in siblings and first cousins with sickle cell disease. In the cases, 10 of 36 siblings and first cousins with sickle cell disease had a history of strokes, versus 3 of 24 siblings and first cousins with sickle cell disease in the controls, Odds Ratio 2.7 (95% confidence interval, 0.6, 14.3).

Strokes occur more frequently in families where a sibling or first cousin with sickle cell disease had a stroke. To fully explore the hypothesis that strokes in sickle cell disease have a genetic component, we are pursuing linkage analysis in famlies with two or more relatives with sickle cell disease and strokes.