RESUMO
OBJECTIVE: To understand motivations, educational needs, and concerns of individuals contemplating whole-exome sequencing (WES) and determine what amount of genetic information might be obtained by sequencing a generally healthy cohort so as to more effectively counsel future patients. PATIENTS AND METHODS: From 2012 to 2014, 40 medically educated, generally healthy scientists at Mayo Clinic were invited to have WES conducted on a research basis; 26 agreed to be in a drawing from which 10 participants were selected. The study involved pre- and posttest genetic counseling and completion of 4 surveys related to the experience and outcomes. Whole-exome sequencing was conducted on DNA from blood from each person. RESULTS: Most variants (76,305 per person; range, 74,505-77,387) were known benign allelic variants, variants in genes of unknown function, or variants of uncertain significance in genes of known function. The results of suspected pathogenic/pathogenic variants in Mendelian disorders and pharmacogenomic variants were disclosed. The mean number of suspected pathogenic/pathogenic variants was 2.2 per person (range, 1-4). Four pharmacogenomic genes were included for reporting; variants were found in 9 of 10 participants. CONCLUSION: This study provides data that may be useful in establishing reality-based patient expectations, outlines specific points to cover during counseling, and increases confidence in the feasibility of providing adequate preparation and counseling for WES in generally healthy individuals.
Assuntos
Atitude do Pessoal de Saúde , Exoma , Aconselhamento Genético/métodos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Seleção de Pacientes , Projetos de Pesquisa , Análise de Sequência de DNA/métodosAssuntos
Biomarcadores Tumorais/genética , Instabilidade Cromossômica , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Marcadores Genéticos , Humanos , Repetições de MicrossatélitesRESUMO
Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for â¼80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3' EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation.
Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Deleção de Sequência , Adulto , Idoso , Neoplasias do Colo/genética , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Reação em Cadeia da Ligase , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (+/-SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0+/-14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2+/-15.5mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.