Segregation Analysis of Restless Legs Syndrome: Possible Evidence for a Major Gene in a Family Study Using Blinded Diagnoses

Abstract

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.

Genetics of restless legs syndrome (RLS): State-of-the-art and future directions

“…Lack of evidence for a major gene controlling age of onset, indicated that nongenetic causes of RLS may exist and that RLS is a complex disorder. 36 In general, one has to consider that all the studies on a genetic model are estimates and averages across a probably heterogeneous set of families and are sensitive to various biases in the way the data are collected. There is always a possibility of bias in the ascertained cohort and the generalizability of these findings to the RLS population at large may be limited.…”

A novel locus for restless legs syndrome maps to chromosome 19p in an Irish pedigree

“…To date, no causative gene mutation has been detected in these loci despite convincing linkage analysis results, often from the study of a single family. Segregation studies have reported that familial RLS is consistent with a single major locus when age of onset is not considered [35,36]. However, the absence of evidence for a major gene controlling age of onset suggests that non-genetic causes of RLS may exist and that RLS is a complex disorder [36].…”

“…Segregation studies have reported that familial RLS is consistent with a single major locus when age of onset is not considered [35,36]. However, the absence of evidence for a major gene controlling age of onset suggests that non-genetic causes of RLS may exist and that RLS is a complex disorder [36]. Indeed, one of the recent linkage reports identified a family that may potentially carry low-penetrance disease alleles from two distinct loci [21].…”

“…Results for all ten questions were compiled to give an overall score. In accordance with the scoring system, severity was categorised into four groups scoring system: mild (0-10), moderate (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), severe (21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and very severe (31)(32)(33)(34)(35)(36)(37)(38)(39)(40).…”

Evidence for linkage of restless legs syndrome to chromosome 9p

“…6 RLS is characterized by high familial aggregation. [7][8][9] A heritability of approximately 50% 10 and an autosomal dominant mode of inheritance is most likely, 11,12 but no gene mutation has yet been identified in primary RLS. However, within the past 6 years, five gene loci for RLS have been reported on chromosomes 12q12-21 (RLS1), 13 14q13-21 (RLS2), 14 9p24-22 (RLS3), 15 2q33 (RLS4), 16 and 20p13 (RLS5).…”