The Journal of clinical endocrinology and metabolism · 2013
Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAnodontiaCohort StudiesDNA HelicasesDNA-Binding ProteinsExtracellular Matrix ProteinsFemaleFibroblast Growth Factor 8Finger PhalangesGenetic Association StudiesGenetic TestingHealth Care CostsHearing LossHumansKallmann SyndromeMaleMassachusettsMutationNerve Tissue ProteinsPolymorphism, GeneticReceptor, Fibroblast Growth Factor, Type 1Severity of Illness IndexSignal TransductionSynkinesis