A Review of the Genetics of Intracranial Berry Aneurysms and Implications for Genetic Counseling

Abstract

Here we review the current understanding of the genetic architecture of intracranial berry aneurysms (IBA) to aid in the genetic counseling of patients at risk for this condition. The familial subtype of IBA, familial intracranial aneurysms (FIA), is associated with increased frequency of IBA, increased risk of rupture, and increased morbidity and mortality after rupture. Family history is the strongest predictor for the development of IBA. However, a genetic test is not yet available to assess risk within a family. Studies using linkage analysis, genome-wide association, and next-generation sequencing have found several candidate loci and genes associated with disease onset, but have not conclusively implicated a single gene. In addition to family history, a separate or concurrent diagnosis of autosomal dominant polycystic kidney disease is a strong genetic risk factor for IBA formation. We also discuss the relative risk for developing IBA in several Mendelian syndromes including vascular Ehlers-Danlos syndrome, Marfan syndrome, Neurofibromatosis Type I, and Loeys-Dietz syndrome.

Keywords: Autosomal dominant polycystic kidney disease; Ehlers-Danlos syndrome; Familial intracranial aneurysms; Genome-wide association study; Intracranial berry aneurysms; Linkage analysis; Loeys-Dietz syndrome; Marfan syndrome; Neurofibromatosis type I; Whole-exome sequencing.

Fig. 1

Pedigrees of three families diagnosed with familial intracranial aneurysms suggesting dominant inheritance (a), and inheritance consistent with dominant or X-linked transmission (b). Part (c) shows a sporadic case of an intracranial berry aneurysm; its onset in childhood in the absence of known environmental risk factors is consistent with a major genetic risk factor such as a de novo pathogenic variant