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

Author(s)

Trarbach, Ericka Barbosa ^[1] ; Teles, Milena Gurgel ^[1] ; Frade Costa, Elaine Maria ^[1] ; Abreu, Ana Paula ^[1] ; Garmes, Heraldo Mendes ^{[2, 3]} ; Guerra-Junior, Gil ^{[2, 3]} ; Matias Baptista, Maria Tereza ^{[2, 3]} ; de Castro, Margaret ^[4] ; Mendonca, Berenice Bilharinho ^[1] ; Latronico, Ana Claudia ^[1]

Affiliation

^[1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol, Disciplina Endocrinol, Hosp Clin, Fac Med, LIM42, BR-05403900 Sao Paulo - Brazil

^[2] Univ Estadual Campinas, Dept Pediat, Disciplina Endocrinol & Metabol, Fac Ciencias Med, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Dept Clin Med, Disciplina Endocrinol & Metabol, Fac Ciencias Med, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Dept Med Interna, Div Endocrinol, Fac Med Ribeirao Preto, BR-05403900 Sao Paulo - Brazil

• Document type: Journal article
• Source: CLINICAL ENDOCRINOLOGY; v. 72, n. 3, p. 371-376, MAR 2010.
• Web of Science Citations: 13

Abstract

P>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. (AU)

• FAPESP's process: 05/04726-0 - Molecular characterization of congenital endocrine diseases that affect growth and development
• Grantee: Ana Claudia Latronico Xavier
• Support Opportunities: Research Projects - Thematic Grants