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

• Published in: Clinical endocrinology (Oxford) Vol. 72; no. 3; pp. 371 - 376
• Main Authors: Trarbach, Ericka Barbosa, Teles, Milena Gurgel, Costa, Elaine Maria Frade, Abreu, Ana Paula, Garmes, Heraldo Mendes, Guerra Junior, Gil, Baptista, Maria Tereza Matias, De Castro, Margaret, Mendonca, Berenice Bilharinho, Latronico, Ana Claudia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2010; Blackwell; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Biological and medical sciences; Brazil; Chromosome Disorders - genetics; Endocrinopathies; Exons; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Dosage; Genes; Humans; Hypogonadism - genetics; Hypothalamus. Hypophysis. Epiphysis (diseases); Ligase Chain Reaction; Male; Medical sciences; Middle Aged; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Vertebrates: endocrinology; Young Adult; Brazil; Endocrinopathy; Human; Hypogonadotropic hypogonadism; Hypothalamic diseases; Patient; Medical screening; Genital diseases; Genetic disease; Multiplex ligation dependent probe amplification; Gene; Autosomal character; Deletion; Genetics; Diagnosis; Inheritance(genetics); Detection; Fibroblast growth factor receptor 1; Endocrinology
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2009.03642.x

Summary 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.