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Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

Lookup NU author(s): Dr Ravikumar Balasubramanian, Dr Richard Quinton


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Context: 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.Subjects: 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.Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured.Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicularvolumes(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), dentalagenesis(FGF8/FGFR1), digital bony abnormalities(FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

Publication metadata

Author(s): Costa-Barbosa FA, Balasubramanian R, Keefe KW, Shaw ND, Al-Tassan N, Plummer L, Dwyer AA, Buck CL, Choi JH, Seminara SB, Quinton R, Monies D, Meyer B, Hall JE, Pitteloud N, Crowley WF

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2013

Volume: 98

Issue: 5

Pages: E943-E953

Print publication date: 01/05/2013

Online publication date: 26/03/2013

Acceptance date: 26/02/2013

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: The Endocrine Society


DOI: 10.1210/jc.2012-4116


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