title: When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).
abstract: BACKGROUND
  A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations.
  
  
  OBJECTIVE
  The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR.
  
  
  METHODS
  Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes.
  
  
  RESULTS
  The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes.
  
  
  CONCLUSIONS
  In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.
authors: Harvard Center for Reproductive Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, BHX 504, Boston, Massachusetts 02114, USA.
authors: Elena
authors: E
authors: Gianetti
authors: Janet E
authors: JE
authors: Hall
authors: Margaret G
authors: MG
authors: Au
authors: Ursula B
authors: UB
authors: Kaiser
authors: Richard
authors: R
authors: Quinton
authors: Jane A
authors: JA
authors: Stewart
authors: Daniel L
authors: DL
authors: Metzger
authors: Nelly
authors: N
authors: Pitteloud
authors: Veronica
authors: V
authors: Mericq
authors: Paulina M
authors: PM
authors: Merino
authors: Lynne L
authors: LL
authors: Levitsky
authors: Louise
authors: L
authors: Izatt
authors: Mariarosaria
authors: M
authors: Lang-Muritano
authors: Victor Y
authors: VY
authors: Fujimoto
authors: Robert G
authors: RG
authors: Dluhy
authors: Matthew L
authors: ML
authors: Chase
authors: William F
authors: WF
authors: Crowley
authors: Lacey
authors: L
authors: Plummer
authors: Stephanie B
authors: SB
authors: Seminara
mesh_terms: D000293:Adolescent; D000328:Adult; D000568:Amenorrhea / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005006:Ethnicity; D005260:Female; D040741:Genetic Load; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007027:Hypothalamic Diseases / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011628:Puberty, Delayed / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics* / Q000502:physiology*; D055815:Young Adult
chemical_list: D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D004247:DNA