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Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.

  • Costa-Barbosa, Flavia Amanda1
  • Balasubramanian, Ravikumar
  • Keefe, Kimberly W
  • Shaw, Natalie D
  • Al-Tassan, Nada
  • Plummer, Lacey
  • Dwyer, Andrew A
  • Buck, Cassandra L
  • Choi, Jin-Ho
  • Seminara, Stephanie B
  • Quinton, Richard
  • Monies, Dorota
  • Meyer, Brian
  • Hall, Janet E
  • Pitteloud, Nelly
  • Crowley, William F Jr
  • 1 Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Published Article
The Journal of Clinical Endocrinology & Metabolism
The Endocrine Society
Publication Date
May 01, 2013
DOI: 10.1210/jc.2012-4116
PMID: 23533228


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. The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. 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. Reproductive and nonreproductive phenotypes within each genetic group were measured. 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. 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.

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