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1.
JCO Precis Oncol ; 8: e2400106, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39013133

RESUMO

PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.


Assuntos
Predisposição Genética para Doença , Humanos , Feminino , Pessoa de Meia-Idade , Adulto , Masculino , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Sequenciamento do Exoma , Guias de Prática Clínica como Assunto , Idoso , Testes Genéticos/métodos , Adulto Jovem , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Heterozigoto
2.
Orphanet J Rare Dis ; 19(1): 216, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38790019

RESUMO

BACKGROUND: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). CONCLUSION: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento do Exoma/métodos , Exoma/genética , Adulto Jovem , Doenças Raras/genética , Doenças Raras/diagnóstico , Idoso , Adolescente , Sequenciamento Completo do Genoma/métodos
4.
Lung ; 202(2): 151-156, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38461429

RESUMO

BACKGROUND: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes. METHODS: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis. RESULTS: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations. CONCLUSION: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/genética , Fibrose Pulmonar/complicações , Tomografia Computadorizada por Raios X/métodos , Doenças Pulmonares Intersticiais/diagnóstico , Fibrose , Testes Genéticos , Tensoativos , Pulmão/diagnóstico por imagem , Pulmão/patologia
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