title: IGSF1 variants in boys with familial delayed puberty.
abstract: The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein mainly expressed in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). As this syndrome was discovered in patients with CeH, it is unknown whether IGSF1 mutations might also cause delayed puberty without CeH. We therefore determined the prevalence of IGSF1 sequence variants in 30 patients with an apparent X-linked form of constitutional delay of growth and puberty (CDGP). In four families, we discovered three novel variants of unknown clinical significance (VUCSs), with possible pathogenicity predicted by in silico analysis. However, the genotype did not fully cosegregate with CDGP, all three VUCSs showed normal plasma membrane expression in transfected HEK293 cells, and no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. The observation of hyperprolactinemia in two carriers remains unexplained.
  
  
  CONCLUSIONS
  There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands, sdjoustra@lumc.nl.
authors.forename: Sjoerd D
authors.initials: SD
authors.lastname: Joustra
authors.forename: Karoliina
authors.initials: K
authors.lastname: Wehkalampi
authors.forename: Wilma
authors.initials: W
authors.lastname: Oostdijk
authors.forename: Nienke R
authors.initials: NR
authors.lastname: Biermasz
authors.forename: Sasha
authors.initials: S
authors.lastname: Howard
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Silander
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
authors.forename: Monique
authors.initials: M
authors.lastname: Losekoot
mesh_terms: D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011628:Puberty, Delayed / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins