A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism

Abstract

Context: Delayed puberty (DP) is a common issue and, in the absence of an underlying condition, is typically self limited. Alhough DP seems to be heritable, no specific genetic cause for DP has yet been reported. In contrast, many genetic causes have been found for idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder characterized by absent or stalled pubertal development.

Objective: The objective of this retrospective study, conducted at academic medical centers, was to determine whether variants in IHH genes contribute to the pathogenesis of DP.

Subjects and outcome measures: Potentially pathogenic variants in IHH genes were identified in two cohorts: 1) DP family members of an IHH proband previously found to have a variant in an IHH gene, with unaffected family members serving as controls, and 2) DP individuals with no family history of IHH, with ethnically matched control subjects drawn from the Exome Aggregation Consortium.

Results: In pedigrees with an IHH proband, the proband's variant was shared by 53% (10/19) of DP family members vs 12% (4/33) of unaffected family members (P = .003). In DP subjects with no family history of IHH, 14% (8/56) had potentially pathogenic variants in IHH genes vs 5.6% (1 907/33 855) of controls (P = .01). Potentially pathogenic variants were found in multiple DP subjects for the genes IL17RD and TAC3.

Conclusions: These findings suggest that variants in IHH genes can contribute to the pathogenesis of self-limited DP. Thus, at least in some cases, self-limited DP shares an underlying pathophysiology with IHH.

Figure 1.

Ascertainment of family members with delayed puberty and normal pubertal timing in pedigrees with IHH probands. N, number of individuals specified in associated rectangle. *, Three pedigrees were excluded: one in which the IHH proband had a potentially pathogenic variant in KAL1 and DNA was available only for male family members, and two in which the IHH probands had biallelic variants in GNRHR and DNA was available for only the proband's parents. †, P = .003.

Figure 2.

Examples of pedigrees with potentially pathogenic variants that segregate with IHH and delayed puberty (Pedigrees 3 and 11 from Table 1) and of a pedigree with a potentially pathogenic variant that does not (Pedigree 1). Arrows identify the IHH proband. Genotypes of subjects for whom DNA was available are listed below each subject's symbol. Plus sign (+) indicates the wild-type allele. Squares represent males; circles represent females.