Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association

Abstract

Meniere's disease (MD) is a disorder of the inner ear characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. Most MD cases are sporadic, but 5-15% of patients are familial following an autosomal dominant mode of inheritance with incomplete penetrance. We have previously identified a candidate gene region for MD on chromosome 12p12.3 using linkage analysis. We genotyped 15 Swedish families segregating familial MD (FMD) to further clarify the role of chromosome 12p in a larger cohort of families. Highly polymorphic marker loci were analyzed over the 16-Mb candidate region in affected and healthy family members as well as in control subjects. The results revealed allelic association between FMD and several individual polymorphic marker alleles and single-nucleotide polymorphisms. Moreover, a common three-marker haplotype spanning 1.48 Mb co-segregates with FMD in 60% of the families investigated, forming the core of a possible ancestral haplotype associated with FMD in Sweden.

Finnish familial Meniere disease is not linked to chromosome 12p12.3, and anticipation and cosegregation with migraine are not common findings

“…Further evidence for Swedish FMD susceptibility locus was obtained by Gabriková et al using haplotype analysis in 15 Swedish families (including the families used in the work of Klar et al), they identified a 1.48-Mb region on chromosome 12p12.3 that associated with FMD in 60% of the families. 30 Our series nevertheless failed to provide any evidence of linkage to chromosome 12p12.3. Given that an obvious earlier onset in subsequent generations was seen in two of the three families studied by Klar et al, the lack of both anticipation and linkage to chromosome 12p12.3 in the Finnish families may suggest locus heterogeneity in FMD.…”

High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland

“…This could have led to the underestimation of especially the amount of recessive families. Also, as there can be a delay between the manifestations of the first symptoms and the whole triad of MD [9], some of the relatives with part of the triad may be in the early stages of MD.…”

“…FMD has been linked to chromosome 12p12.3 in affected Swedish families [9,13], but no such linkage was seen in Finnish MD families [11]. Quite recently a possible linkage to chromosome 5 and a second locus on chromosome 12 were observed in an analysis of 17 German FMD families [3].…”

Genetics of Recurrent Vertigo and Vestibular Disorders

“…This region was analyzed in 15 families with several cases segregating FMD in at least two patients. The confirmed allelic association defines an haplotype in 12p12.3 between the markers D12S373 and GT27 [57]. Two genes are located in the region: RERG/RAS-like gene (RERGL) and PIK3C2G gene; however, none of these genes show any alterations in the coding sequences in patients with FMD.…”