title: Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.
abstract: BACKGROUND
  The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening.
  
  
  OBJECTIVE
  The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations.
  
  
  METHODS
  Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes.
  
  
  METHODS
  Reproductive and nonreproductive phenotypes within each genetic group were measured.
  
  
  RESULTS
  Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors.
  
  
  CONCLUSIONS
  Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Flavia Amanda
authors.initials: FA
authors.lastname: Costa-Barbosa
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Kimberly W
authors.initials: KW
authors.lastname: Keefe
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Shaw
authors.forename: Nada
authors.initials: N
authors.lastname: Al-Tassan
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Dwyer
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Buck
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.forename: Brian
authors.initials: B
authors.lastname: Meyer
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000328:Adult; D000848:Anodontia / Q000209:etiology; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism; D050278:Finger Phalanges / Q000002:abnormalities; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000191:economics; D017048:Health Care Costs; D034381:Hearing Loss / Q000209:etiology; D006801:Humans; D017436:Kallmann Syndrome / Q000191:economics / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008404:Massachusetts; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D046608:Synkinesis / Q000209:etiology
chemical_list: C076266:ANOS1 protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; C496456:FGF8 protein, human; D009419:Nerve Tissue Proteins; D051524:Fibroblast Growth Factor 8; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D004265:DNA Helicases; C491434:CHD7 protein, human