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Is There an Inherited Contribution to Risk for Sporadic Unilateral Vestibular Schwannoma? Evidence of Familial Clustering

Object Unlike the autosomal dominant inheritance of neurofibromatosis 2, there are no known inherited risk factors for sporadic, unilateral vestibular schwannoma (VS), which comprise most VS cases. The authors tested a hypothesis positing a genetic contribution to predisposition to these lesions by analyzing familial clustering of cases. Methods Familial clustering of individuals with unilateral VS was analyzed in two independent genealogical resources with linked diagnosis data: the Veterans Health Administration Genealogy Resource and the Utah Population Database. Tests for excess relatedness, estimation of relative risks (RRs) in close and distant relatives, and identification of pedigrees with a significant excess of unilateral VS among descendants were performed. Results The average pairwise relatedness of the Veterans Health Administration Genealogy Resource VS cases significantly exceeded the expected relatedness (p = 0.016), even when close relationships were ignored (p = 0.002). RR for third- and fifth-degree relatives developing VS were significantly elevated (RR, 60.83; p = 0.0005; 95% confidence interval [CI], 7.37–219.73) and (RR, 11.88; p = 0.013; 95% CI, 1.44–42.90), respectively. No VS-affected first-, second-, or fourth-degree relatives were observed. In the Utah Population Database population, no first- or second-degree relatives with VS were observed. RR for fifth-degree relatives developing VS was significantly elevated (RR, 2.23; p = 0.009; 95% CI, 1.15–3.90). Conclusion These results provide strong evidence for an inherited predisposition to sporadic, unilateral VS. This study exhibits the value of genealogical resources with linked medical data for examining hypotheses regarding inherited predisposition. The high-risk unilateral VS pedigrees identified in two independent resources provide a powerful means of pursuing predisposition gene identification.