Segregation analysis of restless legs syndrome: possible evidence for a major gene in a family study using blinded diagnoses.
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.


CONCLUSIONS
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.
Mathias
Rasika A
RA
Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
Hening
Wayne
W
Washburn
Mystinna
M
Allen
Richard P
RP
Lesage
Suzanne
S
Wilson
Alexander F
AF
Earley
Christopher J
CJ
D000368:Aged; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D040582:Inheritance Patterns; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010375:Pedigree; D010641:Phenotype; D012148:Restless Legs Syndrome / Q000175:diagnosis / Q000235:genetics*