Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

• Published in: The journal of clinical endocrinology and metabolism Vol. 98; no. 5; pp. E943 - E953
• Main Authors: Costa-Barbosa, Flavia Amanda, 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.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.05.2013; Copyright by The Endocrine Society; Endocrine Society
• Subjects: Adult; Anodontia - etiology; Cleft lip/palate; Cohort Studies; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibroblast growth factor 8; Fibroblast Growth Factor 8 - genetics; Fibroblast Growth Factor 8 - metabolism; Fibroblast growth factor receptor 1; Finger Phalanges - abnormalities; Genes; Genetic Association Studies; Genetic screening; Genetic testing; Genetic Testing - economics; Health Care Costs; Hearing loss; Hearing Loss - etiology; Humans; JCEM Online: Advances in Genetics; Kallmann Syndrome - economics; Kallmann Syndrome - genetics; Kallmann Syndrome - metabolism; Kallmann Syndrome - physiopathology; Kallmann's syndrome; Male; Massachusetts; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phenotypes; Point mutation; Polymorphism, Genetic; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Severity of Illness Index; Signal Transduction; Statistical analysis; Synkinesis - etiology; Massachusetts
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2012-4116

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 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.