title: Identification of HESX1 mutations in Kallmann syndrome.
abstract: OBJECTIVE
  To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS).
  
  
  METHODS
  Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  Two hundred seventeen patients with IHH/KS and 192 controls.
  
  
  METHODS
  Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made.
  
  
  METHODS
  Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment.
  
  
  RESULTS
  Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present.
  
  
  CONCLUSIONS
  HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.
authors: Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology, Infertility, and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors: Kayce
authors: K
authors: Newbern
authors: Nithya
authors: N
authors: Natrajan
authors: Hyung-Goo
authors: HG
authors: Kim
authors: Lynn P
authors: LP
authors: Chorich
authors: Lisa M
authors: LM
authors: Halvorson
authors: Richard S
authors: RS
authors: Cameron
authors: Lawrence C
authors: LC
authors: Layman
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017436:Kallmann Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins