The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome

Samuel D. Quaynor, Hyung Goo Kim, Elizabeth M. Cappello, Tiera Williams, Lynn P. Chorich, David P. Bick, Richard J. Sherins, Lawrence C Layman

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Objective: To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). Design: Molecular analysis of DNA in IHH/KS patients. Setting: Academic medical center. Patient(s): Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2). Intervention(s): DNA from IHH/KS patients was subjected to polymerase chain reaction-based DNA sequencing of the 13 most common genes (KAL1, GNRHR, FGFR1, KISS1R, TAC3, TACR3, FGF8, PROKR2, PROK2, CHD7, NELF, GNRH1, and WDR11). Main Outcome Measure(s): The identification of mutations absent in ≥188 ethnically matched controls. Both SIFT (sorting intolerant from tolerant) and conservation among orthologs provided supportive evidence for pathologic roles. Result(s): In group 1, 6 (25%) of 24 IHH/KS patients had a heterozygous mutation in a second gene, and in group 2, 13 (54.2%) of 24 had a mutation in at least one gene, but none had digenic mutations. In group 2, 7 (29.2%) of 24 had a mutation considered sufficient to cause the phenotype. Conclusion(s): When the 13 most common IHH/KS genes are studied, the overall prevalence of digenic gene mutations in IHH/KS was 12.5%. In addition, approximately 30% of patients without a known mutation had a mutation in a single gene. With the current state of knowledge, these findings suggest that most IHH/KS patients have a monogenic etiology.

Original languageEnglish (US)
JournalFertility and sterility
Volume96
Issue number6
DOIs
StatePublished - Jan 1 2011

Keywords

  • Digenic mutations
  • Kallmann syndrome
  • idiopathic hypogonadotropic hypogonadism

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

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