Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome

Samuel D. Quaynor, Maggie E. Bosley, Christina G. Duckworth, Kelsey R. Porter, Soo Hyun Kim, Hyung Goo Kim, Lynn P. Chorich, Megan E. Sullivan, Jeong Hyeon Choi, Richard S. Cameron, Lawrence C. Layman

Research output: Contribution to journalArticle

18 Scopus citations


The genetic basis is unknown for ∼60% of normosmic hypogonadotropic hypogonadism (nHH)/Kallmann syndrome (KS). DNAs from (17 male and 31 female) nHH/KS patients were analyzed by targeted next generation sequencing (NGS) of 261 genes involved in hypothalamic, pituitary, and/or olfactory pathways, or suggested by chromosome rearrangements. Selected variants were subjected to Sanger DNA sequencing, the gold standard. The frequency of Sanger-confirmed variants was determined using the ExAC database. Variants were classified as likely pathogenic (frameshift, nonsense, and splice site) or predicted pathogenic (nonsynonymous missense). Two novel FGFR1 mutations were identified, as were 18 new candidate genes including: AMN1, CCKBR, CRY1, CXCR4, FGF13, GAP43, GLI3, JAG1, NOS1, MASTL, NOTCH1, NRP2, PALM2, PDE3A, PLEKHA5, RD3, and TRAPPC9, and TSPAN11. Digenic and trigenic variants were found in 8/48 (16.7%) and 1/48 (2.1%) patients, respectively. NGS with confirmation by Sanger sequencing resulted in the identification of new causative FGFR1 gene mutations and suggested 18 new candidate genes in nHH/KS.

Original languageEnglish (US)
Pages (from-to)86-96
Number of pages11
JournalMolecular and Cellular Endocrinology
StatePublished - Dec 5 2016



  • Delayed puberty
  • GnRH deficiency
  • Hypogonadotropic hypogonadism
  • Kallmann syndrome
  • Next generation DNA sequencing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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