title: The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
abstract: Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are clinically and genetically heterogeneous disorders caused by a deficiency of gonadotrophin-releasing hormone (GnRH). Mutations in three genes--KAL1, GNRHR and FGFR1--account for 15-20% of all causes of IHH/KS. Nearly all mutations are point mutations identified by traditional PCR-based DNA sequencing. The relatively new method of multiplex ligation-dependent probe amplification (MLPA) has been successful for detecting intragenic deletions in other genetic diseases. We hypothesized that MLPA would detect intragenic deletions in approximately 15-20% of our cohort of IHH/KS patients. Fifty-four IHH/KS patients were studied for KAL1 deletions and 100 were studied for an autosomal panel of FGFR1, GNRH1, GNRHR, GPR54 and NELF gene deletions. Of all male and female subjects screened, 4/54 (7.4%) had KAL1 deletions. If only anosmic males were considered, 4/33 (12.1%) had KAL1 deletions. No deletions were identified in any of the autosomal genes in 100 IHH/KS patients. We believe this to be the first study to use MLPA to identify intragenic deletions in IHH/KS patients. Our results indicate approximately 12% of KS males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in IHH/KS.
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Medical College of Georgia, Augusta, GA, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Pedersen-White
authors.forename: Lynn P
authors.initials: LP
authors.lastname: Chorich
authors.forename: David P
authors.initials: DP
authors.lastname: Bick
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sherins
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Layman
mesh_terms: D000293:Adolescent; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D000857:Olfaction Disorders / Q000150:complications / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; C118688:KISS1R protein, human; C411985:NSMF protein, human; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D014157:Transcription Factors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1