title: Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1.
abstract: OBJECTIVE
  Congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome) or with normal sense of smell is a heterogeneous genetic disorder caused by defects in the synthesis, secretion and action of gonadotrophin-releasing hormone (GnRH). Mutations involving autosomal genes have been identified in approximately 30% of all cases of hypogonadotropic hypogonadism. However, most studies that screened patients with hypogonadotropic hypogonadism for gene mutations did not include gene dosage methodologies. Therefore, it remains to be determined whether patients without detected point mutation carried a heterozygous deletion of one or more exons.
  
  
  METHODS
  We used the multiplex ligation-dependent probe amplification (MLPA) assay to evaluate the potential contribution of heterozygous deletions of FGFR1, GnRH1, GnRHR, GPR54 and NELF genes in the aetiology of GnRH deficiency.
  
  
  METHODS
  We studied a mutation-negative cohort of 135 patients, 80 with Kallmann syndrome and 55 with normosmic hypogonadotropic hypogonadism.
  
  
  RESULTS
  One large heterozygous deletion involving all FGFR1 exons was identified in a female patient with sporadic normosmic hypogonadotropic hypogonadism and mild dimorphisms as ogival palate and cavus foot. FGFR1 hemizygosity was confirmed by gene dosage with comparative multiplex and real-time PCRs.
  
  
  CONCLUSIONS
  FGFR1 or other autosomal gene deletion is a possible but very rare event and does not account for a significant number of sporadic or inherited cases of isolated GnRH deficiency.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42 da Disciplina de Endocrinologia do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. trarbach@hotmail.com
authors.forename: Ericka Barbosa
authors.initials: EB
authors.lastname: Trarbach
authors.forename: Milena Gurgel
authors.initials: MG
authors.lastname: Teles
authors.forename: Elaine Maria Frade
authors.initials: EM
authors.lastname: Costa
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.forename: Heraldo Mendes
authors.initials: HM
authors.lastname: Garmes
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra
authors.forename: Maria Tereza Matias
authors.initials: MT
authors.lastname: Baptista
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Berenice Bilharinho
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil; D025063:Chromosome Disorders / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D022521:Ligase Chain Reaction; D008297:Male; D008875:Middle Aged; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D051496:Receptor, Fibroblast Growth Factor, Type 1