Background-Epidemiological survey studies have suggested that a large fraction of the adult population, from 5 to more than 10%, have symptoms of restless legs syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can "mimic" the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS.

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Objective: The objective of this study was to ascertain the most likely inheritance pattern of restless legs syndrome (RLS) using segregation analysis. Methods: Probands were RLS patients presenting to the Neurology and Sleep clinics of the Johns-Hopkins Bayview medical center with willing first and second degree relatives. Blinded diagnosis was made in those who exhibited the four diagnostic features of RLS. Analysis was performed on RLS as a dichotomous trait and considering age of onset models on 590 phenotyped subjects from 77 pedigrees. Results: All non-genetic models were rejected considering RLS as a dichotomous trait. A single locus Mendelian dominant model with gender as a covariate had best fit with allele frequency of 0.077 and complete penetrance. RLS frequency in non-carrier subjects was estimated to be 0.14. Two underlying distributions of age of onset, with a possible dichotomy at 26.3 years, were identified. Contrary to the results for RLS as a dichotomous trait, age of onset models did not indicate single major gene inheritance. Conclusion: This segregation analysis suggests that the pattern of segregation is consistent with that of a single major locus, when RLS is treated as a dichotomous trait without considering age of onset. The high rate of phenocopies matches known population frequencies and taken with significant residual familial effects and the lack of evidence for a major gene controlling age of onset, indicates that non-genetic causes of RLS may exist and RLS is a complex disorder.

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