Restless Legs Syndrome, Susceptibility To, 8

Description

Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003).

For additional information and a discussion of heterogeneity of restless legs syndrome, see RLS1 (102300).

Mapping

Weissbach et al. (2012) performed genomewide linkage analysis in a 4-generation pedigree segregating autosomal dominantly inherited restless legs syndrome. Of a total of 27 individuals, 7 were definitely affected, 3 who fulfilled only 2 of the 4 essential criteria were considered possibly affected, and 17 were unaffected. Whole-exome sequencing was then performed on 2 definitely affected cousins, followed by systematic validation. Weissbach et al. (2012) detected a missense mutation in the PCDHA3 gene (606309.0001) on chromosome 5q31 that segregated with the phenotype in the family. They also identified 2 novel missense and 1 splice site variant, respectively, in the WWC2, ATRN (603130), and FAT2 (604269) genes that segregated with RLS in the family. All 4 exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed 3 additional rare missense variants (frequency less than 1%) of unknown pathogenicity in 2 patients and 1 control. There was significant enrichment for rare missense variants in the PCDHA3 gene in individuals with restless legs syndrome versus unaffected individuals (3.1% versus 0.4%). Weissbach et al. (2012) were careful to suggest that their findings were hypothesis-generating rather than conclusive evidence for PCDHA3 as the cause of restless legs syndrome in these individuals.