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.

MEASUREMENTS:

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.

PATIENTS:

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: Ericka Barbosa Trarbach, Milena Gurgel Teles, Elaine Maria Frade Costa, Ana Paula Abreu, Heraldo Mendes Garmes, Gil Guerra Jr, Maria Tereza Matias Baptista, Margaret de Castro, Berenice Bilharinho Mendonca, Ana Claudia Latronico
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 72 Issue 3 Pg. 371-6 (Mar 2010) ISSN: 1365-2265 [Electronic] England
• PMID: 19489874 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Adolescent
• Adult
• Brazil
• Chromosome Disorders (genetics)
• Exons
• Female
• Gene Deletion
• Gene Dosage
• Humans
• Hypogonadism (genetics)
• Ligase Chain Reaction
• Male
• Middle Aged
• Receptor, Fibroblast Growth Factor, Type 1 (genetics)
• Young Adult