Context: Twin studies indicate that the timing of pubertal onset is under strong genetic control. However, genes controlling pubertal timing in the general population have not yet been identified.
Objective: To facilitate the identification of genes influencing the timing of pubertal growth and maturation, we conducted linkage mapping of constitutional delay of growth and puberty (CDGP), an extreme variant of normal pubertal timing, in extended families.
Participants and methods: Fifty-two families multiply affected with CDGP were genotyped with 383 multiallelic markers. CDGP was defined based on growth charts (the age at onset of growth spurt, peak height velocity, or attaining adult height taking place at least 1.5 sd later than average). Chromosomal regions cosegregating with CDGP were identified with parametric affected-only linkage analysis using CDGP as a dichotomized trait.
Results: The genome-wide scan detected linkage of CDGP to a region on chromosome 2p13-2q13. The two-point heterogeneity LOD (HLOD) score was 1.62 (alpha = 0.27), and the corresponding multipoint HLOD was 2.54 (alpha = 0.31). Fine-mapping the region at 1 cM resolution increased the multipoint HLOD score to 4.44 (alpha = 0.41). The linkage became weaker if family members diagnosed with CDGP without growth data were also included in the analyses.
Conclusions: The pericentromeric region of chromosome 2 harbors a gene predisposing to pubertal delay in multiply affected pedigrees. Our data suggest that this locus may be a component of the internal clock controlling the timing of the onset of puberty.