The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome

Mol Hum Reprod. 2008 Jun;14(6):367-70. doi: 10.1093/molehr/gan027. Epub 2008 May 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Cohort Studies
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Deletion*
  • Gene Frequency
  • Gonadotropin-Releasing Hormone / genetics
  • Heterozygote
  • Humans
  • Hypogonadism / complications
  • Hypogonadism / genetics*
  • Kallmann Syndrome / genetics*
  • Male
  • Nerve Tissue Proteins / genetics
  • Olfaction Disorders / complications
  • Olfaction Disorders / genetics
  • Protein Precursors / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Kisspeptin-1
  • Receptors, LHRH / genetics
  • Sex Characteristics
  • Transcription Factors / genetics

Substances

  • ANOS1 protein, human
  • Extracellular Matrix Proteins
  • GNRHR protein, human
  • KISS1R protein, human
  • NSMF protein, human
  • Nerve Tissue Proteins
  • Protein Precursors
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Receptors, LHRH
  • Transcription Factors
  • progonadoliberin I
  • Gonadotropin-Releasing Hormone
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1