Abstract
Ménière's disease (MD) is a common inner ear disorder which is characterized by recurrent attacks of vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and a sense of fullness in the affected ear. MD is a complex disorder; although six genes have been linked to familial autosomal dominant form of the disease, in many cases, the exact genetic etiology remains elusive. To elucidate the genetic causes of MD in an Iranian family, we performed exome sequencing on all members of the family: consanguineous parents and four children (two affected and two unaffected). Variant filtering was completed using a customized workflow keeping variants based on segregation with MD in autosomal recessive (AR) inheritance pattern, minor allele frequency (MAF), and in-silico prediction of pathogenicity. Analysis revealed that in this family, 970 variants co-segregated with MD in AR pattern, out of which eight variants (one intergenic, four intronic, and three exonic) were extremely rare. The exonic variants included a synonymous substitution in USP3 gene, an in-frame deletion in ZBED2 gene, and a rare, highly conserved deleterious missense alteration in LSAMP gene. The phenotype observed in the proband described here, i.e. vertigo, poor sense of smell, tinnitus, and borderline hearing ability, may originate from aberrant changes in the cerebellum and limbic system due to a deleterious mutation in the LSAMP gene; hence, LSAMP mutation is a possible candidate for the etiology of MD in this family.
Highlights
Diseases which display phenotypic heterogeneity, pleiotropy and incomplete penetrance, often arise from a complex combination of etiological factors, including genetic and environmental components
Whole blood samples were collected from all members of the core family including both individuals affected with ARFMD, unaffected siblings and both parents
The three exonic variants included a synonymous variant in USP3 [MIM:604728] gene, a 3-bp variant in ZBED2 [MIM:615246] gene that was predicted to be a polymorphism, and a highly conserved and predicted deleterious missense variant in limbic system associated membrane protein (LSAMP) [MIM:603241] gene (Table 2)
Summary
Diseases which display phenotypic heterogeneity, pleiotropy and incomplete penetrance, often arise from a complex combination of etiological factors, including genetic and environmental components. As such, these diseases are often hard to characterize and it is difficult to elucidate the genetics and pathophysiology underlying the disease, as is the case with Ménière’s disease (MD [MIM 156000]). MD symptoms mainly affect one ear (unilateral MD); bilateral MD has been reported.[1,5,6] Broadly, MD falls into two clinical categories: definite and probable, with probable being less phenotypically severe.[7] MD usually begins to manifest in the third to the seventh decades of life with a small female predominance, and only a few rare cases have been identified in younger people.[2,7,8]. We conclude that a mutation of the gene encoding the limbic system associated membrane protein (LSAMP) plays a role in ARFMD
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