title: Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome.
abstract: 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.
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States; University of Chicago, Department of Neurology, Chicago, IL, United States.
authors: Samuel D
authors: SD
authors: Quaynor
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Maggie E
authors: ME
authors: Bosley
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Christina G
authors: CG
authors: Duckworth
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Kelsey R
authors: KR
authors: Porter
authors: Molecular Cell Sciences Research Centre, St. George's Medical School, University of London, London, UK.
authors: Soo-Hyun
authors: SH
authors: Kim
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Hyung-Goo
authors: HG
authors: Kim
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Lynn P
authors: LP
authors: Chorich
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Megan E
authors: ME
authors: Sullivan
authors: Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Jeong-Hyeon
authors: JH
authors: Choi
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors: Richard S
authors: RS
authors: Cameron
authors: Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States. Electronic address: lalayman@augusta.edu.
authors: Lawrence C
authors: LC
authors: Layman
mesh_terms: D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype
keywords: Delayed puberty; GnRH deficiency; Hypogonadotropic hypogonadism; Kallmann syndrome; Next generation DNA sequencing