A Genome-Wide Linkage Scan of Familial Benign Recurrent

A Genome-Wide Linkage Scan of Familial Benign Recurrent Vertigo: Linkage to 22q12 with Evidence of Heterogeneity

Hane Lee, Joanna C. Jen, Hui Wang, Zugen Chen, Hafsa Mamsa, Chiara Sabatti, Robert W. Baloh, Stanley F. Nelson

“Benign recurrent vertigo is a common disorder affecting up to 2% of the adult population and may etiologically be related to migraine due to similarities in the clinical spectrum of the phenotypes and a high comorbidity within families. Many families have multiple affected genetically related individuals suggesting familial transmission of the disorder with moderate to high penetrance. While clinically similar to episodic ataxias, there are currently no genes identified which contribute to BRV and no systematic linkage studies performed. In an initial effort to genetically define BRV, we have selected from our Neurology Clinic population a subset of 20 multigenerational families with apparent autosomal dominant transmission, and performed genetic linkage mapping using both parametric and non-parametric approaches. The Affymetrix 10K SNP Mapping Assay was used for the genotyping. Heterogeneity LOD (HLOD) analysis reveals evidence of genetic heterogeneity for BRV and evidence of linkage in a subset of the families to 22q12 (HLOD=4.02). An additional region was identified by non-parametric analysis at 5p15 (LOD=2.63). As migraine is observed substantially more commonly both within the BRV affected individuals and the related family members, it is possible that a form of migraine is allelic to the BRV locus at 22q12. However, testing linkage or the chromosome 22q12 region to a broader migraine/vertigo phenotype by defining affectation status as either migrainous headaches or BRV greatly weakened the linkage signal, and no significant other peaks were detected. Thus, BRV and migraine do not appear to be allelic disorders within these families. We conclude that BRV is a heterogeneous genetic disorder, appears genetically distinct from
migraine with aura, and is linked to 22q12. Additional family and population based linkage and association studies will be needed to determine the causative alleles.”

mvertigo.org/articles/A_Geno … eneity.pdf