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.
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.
Trarbach
Ericka Barbosa
EB
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
Teles
Milena Gurgel
MG
Costa
Elaine Maria Frade
EM
Abreu
Ana Paula
AP
Garmes
Heraldo Mendes
HM
Guerra
Gil
G
Baptista
Maria Tereza Matias
MT
de Castro
Margaret
M
Mendonca
Berenice Bilharinho
BB
Latronico
Ana Claudia
AC
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
D051496:Receptor, Fibroblast Growth Factor, Type 1