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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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Funder referenceFunder name
Harvard University
8UL1TR000170-05Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health)
R01 HD056264National Institutes of Health
R01 HD15788National Institutes of Health
R01 HD42708National Institutes of Health
U54 HD028138National Institutes of Health