A Shared Genetic Basis for Self-Limited Delayed Puberty and Idiopathic Hypogonadotropic Hypogonadism
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CitationZhu, Jia. 2015. A Shared Genetic Basis for Self-Limited Delayed Puberty and Idiopathic Hypogonadotropic Hypogonadism. Doctoral dissertation, Harvard Medical School.
AbstractBackground: Delayed puberty is a common condition and, in the absence of an underlying condition, is self-limited in most cases. Though delayed puberty appears to be heritable, no specific genetic cause has yet been reported. In contrast, many genetic causes have been found for idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder in which defects in GnRH secretion or action lead to absent or stalled pubertal development. We hypothesized that there is a shared genetic basis for both self-limited delayed puberty and IHH.
Methods: We used two approaches to determine if there is genetic overlap between self-limited delayed puberty and IHH. First, in pedigrees with a proband with IHH known to carry a variant in an IHH gene, we performed targeted sequencing to determine whether family members with self-limited delayed puberty were more likely than family members with normal pubertal timing to share the proband’s variant. Second, in probands with self-limited delayed puberty and no family history of IHH, we performed whole-exome sequencing and examined 33,855 ethnically matched controls drawn from the Exome Aggregation Consortium for variants in 21 IHH genes. Variants were characterized as potentially pathogenic based on rarity, severity of mutation, and in silico analyses.
Results: In pedigrees with an IHH proband, the proband’s potentially pathogenic variant was shared by 53% (10/19) of delayed puberty family members vs. 12% (4/33) of unaffected family members (P = 0.003). In delayed puberty 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 = 0.01). Such variants were found at a higher frequency in subjects with self-limited delayed puberty compared to controls in the specific genes IL17RD, TAC3, and TACR3.
Conclusions: For the first time, we report a specific genetic cause for self-limited delayed puberty. These findings suggest that variants in IHH genes can contribute to the pathogenesis of self-limited delayed puberty. Thus, at least in some cases, self-limited delayed puberty shares an underlying pathophysiology with IHH. In addition, our study presents IL17RD, TAC3, and TACR3 as candidate genes for future genetic studies of self-limited delayed puberty and highlights both the benefits and limitations of genetic testing.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:15821591