Genetics of Restless Legs Syndrome

Abstract

The high frequency of positive family history of restless legs syndrome (RLS) in patients diagnosed with this disease, the higher concordance rates in monozygotic compared with dizygotic twins, and the presence of genetic anticipation suggest an important role of genetic factors in RLS. Inheritance RLS patterns, genetic anticipation, the frequency of positive family history of RLS, twin studies, linkage studies in familial RLS, genome‐wide association studies (GWAS), exome sequencing studies, and case–control association studies on candidate genes in RLS, have been the aim of this article. Some variants of several genes have been associated with RLS risk (most of them through GWAS), being the strongest candidates variants of BTBD9, MEIS1, and PTPRD genes. A recent meta‐analysis confirmed these associations and identified 13 new susceptibility loci related to neurodevelopment‐neurogenesis, cell‐junction organisation, axon guidance, locomotor behaviour and DNA repair and maintenance. Results of several recent case–control association studies suggesting a possible contribution of haem‐oxygenase (HMOX1) rs2071746, vitamin D3 receptor (VDR) rs731236, alcohol‐dehydrogenase 1B (ADH1B) rs1229984, and GABA receptor rho3 (GABRR3) rs832032 variants, or the presence of allele 2 of the complex microsatellite repeat Rep1 within the α‐synuclein (SNCA) gene promoter in modifying the risk for RLS, need a replication by further studies. However, the causative gene(s) for RLS has(ve) not been definitively identified.

Key Concepts

  • The role of genetic factors in the aetiology of RLS is suggested by a substantial reported evidence. It is most likely a genetically complex disorder.
  • Although autosomal dominant is the most frequent inheritance pattern of RLS, there have been reported families with autosomal recessive and with non‐Mendelian patterns. This, together with the presence of phenocopies, suggests a role of epigenetic factors.
  • Linkage studies have identified at least 8 genes/loci, most of them in families with apparently autosomal dominant RLS.
  • Classical genome‐wide association studies (GWAS) have shown association of certain variants of PTPRD, BTBD9, MEIS1, MAP2K5/SKOR1 and TOX3 genes with RLS (some of them showed association with PLMs in patients with and without RLS).
  • A recent meta‐analysis of GWAS have confirmed the 6 risk loci found in classical GWAS and described 13 additional genes/loci, most of them related with neurodevelopment‐neurogenesis, cell‐junction organisation, axon guidance, locomotor behaviour and DNA repair and maintenance.
  • An exome sequencing studies have shown a strong association of the BTBD rs9357271 variant with RLS risk has been shown in an exome sequencing study. Other exome sequencing studies in families showed a possible role of PCDHA3 and TRAPPC6B genes on RLS risk, but they need replication.
  • The short size of the series and the lack of replication studies make that the results of candidate genes should be still limited.

Keywords: family history; genetic polymorphisms; genetics; linkage studies; periodic limb movements; restless legs syndrome; risk factors

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Further Reading

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Jiménez‐Jiménez FJ, Alonso‐Navarro H, García‐Martín E, et al. (2015) Neurochemistry of idiopathic restless legs syndrome. 10: 35–44. http://www.touchneurology.com/articles/neurochemistry‐idiopathic‐restless‐legs‐syndrome.

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Jiménez‐Jiménez, Félix Javier, Alonso‐Navarro, Hortensia, García‐Martín, Elena, and Agúndez, José AG(Dec 2018) Genetics of Restless Legs Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028222]