title: A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit (J.Z., R.E.-Y.C., L.P., C.B., S.B.S., Y.-M.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Department of Medicine (M.H.G., J.N.H., Y.-M.C.), Boston Children's Hospital, Boston, Massachusetts 02115; Department of Genetics (M.H.G., J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; Program in Medical and Population Genetics (M.H.G., J.N.H.), Broad Institute, Cambridge, Massachusetts 02142; Division of Endocrinology and Genetics and Genome Biology Program (M.R.P.), Hospital for Sick Children, Toronto, Canada M5G 1X8; and Institute of Medical Science and Departments of Pediatrics and Physiology (M.R.P.), University of Toronto, Toronto, Canada M5S 1A8.
authors: Jia
authors: J
authors: Zhu
authors: Ruth E-Y
authors: RE
authors: Choa
authors: Michael H
authors: MH
authors: Guo
authors: Lacey
authors: L
authors: Plummer
authors: Cassandra
authors: C
authors: Buck
authors: Mark R
authors: MR
authors: Palmert
authors: Joel N
authors: JN
authors: Hirschhorn
authors: Stephanie B
authors: SB
authors: Seminara
authors: Yee-Ming
authors: YM
authors: Chan
mesh_terms: D000293:Adolescent; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D011628:Puberty, Delayed / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D018039:Receptors, Tachykinin / Q000235:genetics; D012189:Retrospective Studies; D015238:Sulfotransferases / Q000235:genetics; D015320:Tachykinins / Q000235:genetics
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D018039:Receptors, Tachykinin; D015320:Tachykinins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D015238:Sulfotransferases; C404189:heparan sulfate 6-O-sulfotransferase
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