RESUMEN
PURPOSE: Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years. METHODS: Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward. RESULTS: The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million. CONCLUSION: Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.
Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/genética , Pruebas Genéticas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Hipertrófica/epidemiología , Niño , Preescolar , Costos y Análisis de Costo , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/economía , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/normas , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Genet Med advance online publication, January 22, 2015; doi:10.1038/gim.2014.205. In the Advance Online Publication version, of this article, there is a mistake on page 2 in the first paragraph of the Materials and Methods section. The sentence beginning "Among 3,459 probands initially referred for HCM genetic testing " the correct number of probands is 3,473 not 3,459. The authors regret the error.
RESUMEN
On August 5, 2013, the South Carolina Department of Health and Environmental Control was notified of a case of acute respiratory failure in a previously healthy woman. A family interview revealed the patient's uncle and cousin had also been hospitalized with similar symptoms in North Carolina. The South Carolina Department of Health and Environmental Control and the North Carolina Division of Public Health collaborated to identify the cause of the respiratory illness cluster and to prevent additional illnesses.
Asunto(s)
Familia , Neumonía por Mycoplasma/diagnóstico , Adulto , Análisis por Conglomerados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycoplasma pneumoniae/aislamiento & purificación , North Carolina , Neumonía por Mycoplasma/terapia , Índice de Severidad de la Enfermedad , South Carolina , Adulto JovenRESUMEN
During DNA replication, stalled replication forks and DSBs arise when the replication fork encounters ICLs (interstrand crosslinks), covalent protein/DNA intermediates or other discontinuities in the template. Recently, homologous recombination proteins have been shown to function in replication-coupled repair of ICLs in conjunction with the Fanconi anemia (FA) regulatory factors FANCD2-FANCI, and, conversely, the FA gene products have been shown to play roles in stalled replication fork rescue even in the absence of ICLs, suggesting a broader role for the FA network than previously appreciated. Here we show that DNA2 helicase/nuclease participates in resection during replication-coupled repair of ICLs and other replication fork stresses. DNA2 knockdowns are deficient in HDR (homology-directed repair) and the S phase checkpoint and exhibit genome instability and sensitivity to agents that cause replication stress. DNA2 is partially redundant with EXO1 in these roles. DNA2 interacts with FANCD2, and cisplatin induces FANCD2 ubiquitylation even in the absence of DNA2. DNA2 and EXO1 deficiency leads to ICL sensitivity but does not increase ICL sensitivity in the absence of FANCD2. This is the first demonstration of the redundancy of human resection nucleases in the HDR step in replication-coupled repair, and suggests that DNA2 may represent a new mediator of the interplay between HDR and the FA/BRCA pathway.