Alternative titles; symbols
Cytogenetic location: 6p21 Genomic coordinates (GRCh38): 6:30,500,001-46,200,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21 | {Restless legs syndrome 6} | 611185 | 2 |
Restless legs syndrome (RLS) is a neurologic disorder characterized by an uncontrollable urge to move the legs during periods of rest. The majority of patients with RLS also have periodic limb movements in sleep, which are characterized by involuntary, highly stereotypical, regularly occurring limb movements that occur during sleep. Limb movements during sleep are more common in otherwise asymptomatic family members of patients with RLS compared to the general population (Stefansson et al., 2007). Thus, periodic limb movements during sleep may serve as an endophenotype for RLS. However, not all patients with RLS have limb movements during sleep, and the majority of individuals with limb movements during sleep do not have waking symptoms of RLS (Winkelman, 2007).
For additional information and a discussion of genetic heterogeneity of RLS, see RLS1 (102300).
In a genomewide association study, Winkelmann et al. (2007) found a significant association between RLS and 2 SNPs (rs9296249 and rs9357271) in the BTBD9 gene (611237) on chromosome 6p21. The findings were confirmed in 2 independent replication studies of 875 and 211 patients, respectively.
In an analysis of 2 independent samples of 306 and 123 Icelandic subjects, respectively, with RLS and periodic limb movements during sleep, Stefansson et al. (2007) found a significant association with the A allele of rs3923809 in the BTBD9 gene. Combining the results with a third patient group from the U.S. yielded an odds ratio of 1.7 (p = 3 x 10(-14)) for this SNP. Combined data from all 546 Icelandic individuals with periodic limb movements during sleep with or without RLS yielded a higher association with the A allele (odds ratio of 1.9; p = 10(-17)). However, there was no association between the A allele of rs3923809 among 229 individuals with RLS without periodic limb movement (35% of total patient sample), suggesting that the authors had identified a genetic determinant of periodic limb movements in sleep.
Winkelman (2007) commented that the report of Stefansson et al. (2007) demonstrated an association of the BTBD9 variant with periodic limb movements in sleep, but not with RLS. Since Winkelmann et al. (2007) did not report on periodic leg movements in sleep, it remained unclear whether the sequence variants they found were true for RLS, leg movements, or some other potential RLS marker.
In a study of 244 patients with restless legs syndrome, including 123 familial probands, Vilarino-Guell et al. (2008) confirmed an association with several SNPs in the BTBD9 gene, including rs3923809.
In a study including 649 RLS patients and 1,230 controls from the Czech Republic, Austria, and Finland, Kemlink et al. (2009) found an association between RLS and rs3923809 in the BTBD9 gene (p = 4.11 x 10(-5); odds ratio of 1.58). The association was found in both familial and sporadic cases.
Vilarino-Guell et al. (2009) found no novel variants in coding regions or within 10 bp of exon-intron boundaries of the BTBD9 gene among 71 RLS probands.
Restless legs syndrome can occur in end-stage renal disease (ESRD), with a prevalence ranging between 18.4 and 45.8% in ESRD patients of European descent (summary by Schormair et al., 2011). In 2 case-control association studies of 200 RLS patients and 443 non-RLS patients both with ESRD of German descent and 141 RLS and 393 non-RLS patients both with ESRD of Greek descent, Schormair et al. (2011) found an association with rs3923809 in the BTBD9 gene: an OR of 1.55, p = 0.001 in the German sample and an OR of 1.33, p = 0.080 in the Greek sample. The combined samples yielded an OR of 1.47, p (corrected) = 0.0013.
Kemlink, D., Polo, O., Frauscher, B., Gschliesser, V., Hogl, B., Poewe, W., Vodicka, P., Vavrova, J., Sonka, K., Nevsimalova, S., Schormair, B., Lichtner, P., Silander, K., Peltonen, L., Gieger, C., Wichmann, H. E., Zimprich, A., Roeske, D., Muller-Myhsok, B., Meitinger, T., Winkelmann, J. Replication of restless legs syndrome loci in three European populations. J. Med. Genet. 46: 315-318, 2009. [PubMed: 19279021] [Full Text: https://doi.org/10.1136/jmg.2008.062992]
Schormair, B., Plag, J., Kaffe, M., Gross, N., Czamara, D., Samtleben, W., Lichtner, P., Strohle, A., Stefanidis, I., Vainas, A., Dardiotis, E., Sakkas, G. K., Gieger, C., Muller-Myhsok, B., Meitinger, T., Heemann, U., Hadjigeorgiou, G. M., Oexle, K., Winkelmann, J. MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease. J. Med. Genet. 48: 462-466, 2011. [PubMed: 21572129] [Full Text: https://doi.org/10.1136/jmg.2010.087858]
Stefansson, H., Rye, D. B., Hicks, A., Petursson, H., Ingason, A., Thorgeirsson, T. E., Palsson, S., Sigmundsson, T., Sigurdsson, A. P., Eiriksdottir, I., Soebech, E., Bliwise, D., and 14 others. A genetic risk factor for periodic limb movements in sleep. New Eng. J. Med. 357: 639-647, 2007. [PubMed: 17634447] [Full Text: https://doi.org/10.1056/NEJMoa072743]
Vilarino-Guell, C., Chai, H., Keeling, B. H., Young, J. E., Rajput, A., Lynch, T., Aasly, J. O., Uitti, R. J., Wszolek, Z. K., Farrer, M. J., Lin, S.-C. MEIS1 p.R272H in familial restless legs syndrome. Neurology 73: 243-245, 2009. [PubMed: 19620614] [Full Text: https://doi.org/10.1212/WNL.0b013e3181ae7c79]
Vilarino-Guell, C., Farrer, M. J., Lin, S.-C. A genetic risk factor for periodic limb movements in sleep. (Letter) New. Eng. J. Med. 358: 425-427, 2008. [PubMed: 18216367] [Full Text: https://doi.org/10.1056/NEJMc072518]
Winkelman, J. W. Periodic limb movements in sleep--endophenotype for restless legs syndrome? (Editorial) New Eng. J. Med. 357: 703-705, 2007. [PubMed: 17634452] [Full Text: https://doi.org/10.1056/NEJMe078129]
Winkelmann, J., Schormair, B., Lichtner, P., Ripke, S., Xiong, L., Jalilzadeh, S., Fulda, S., Putz, B., Eckstein, G., Hauk, S., Trenkwalder, C., Zimprich, A., and 15 others. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nature Genet. 39: 1000-1006, 2007. [PubMed: 17637780] [Full Text: https://doi.org/10.1038/ng2099]