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1.
Clin Transl Gastroenterol ; 12(10): e00414, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34620795

RESUMO

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach. METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers. RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14-5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25-1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, and RAD51C. DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

2.
J Am Heart Assoc ; 10(17): e019887, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34459253

RESUMO

Background Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

4.
BMC Med ; 19(1): 199, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34404389

RESUMO

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

6.
Am J Hum Genet ; 108(7): 1283-1300, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214447

RESUMO

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Análise Mutacional de DNA , Diploide , Biblioteca Gênica , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Saccharomyces cerevisiae/genética
7.
Can Urol Assoc J ; 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34171218

RESUMO

INTRODUCTION: Prostate cancer is a significant cause of cancer mortality. It has been well-established that certain germline pathogenic variants confer both an increased risk of being diagnosed with prostate cancer and dying of prostate cancer.1 There are exciting developments in both the availability of genetic testing and opportunities for improved treatment of patients. On August 19, 2020, the Princess Margaret Cancer Centre in Toronto, Ontario, hosted a virtual retreat, bringing together international experts in urology, medical oncology, radiation oncology, medical genetics, and translational research, as well as a patient representative. We are pleased to provide this manuscript as a review of those proceedings for Canadian clinicians. RECOMMENDATIONS: We drafted several recommendations for future research and policy action based on this meeting:Need for increased access to funding for germline testing for the common genetic disorders associated with increased risk of prostate cancer.A need for increased research into identifying genetic factors influencing risk stratification, treatment response, and outcomes of prostate cancer within Canadian populations at increased genetic risk for prostate cancer.Need for increased awareness about genetic risk factors among the Canadian public.Need for research on patient perspectives and psychosocial outcomes in individuals identified to be at increased genetic risk of prostate cancer.We support the creation of specialized multidisciplinary clinics that specialize in tailored care for patients at increased genetic risk of prostate cancer.

8.
Genet Med ; 23(10): 1961-1968, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34120153

RESUMO

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

9.
JAMA Cardiol ; 6(8): 902-909, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34037665

RESUMO

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants. Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing. Design, Setting, and Participants: This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form. Main Outcomes and Measures: Number of pathogenic or likely pathogenic (P/LP) variants identified. Results: This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen. Conclusions and Relevance: Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.

10.
Prenat Diagn ; 41(9): 1049-1056, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34057205

RESUMO

The probability an individual is a carrier for a recessive disorder despite a negative carrier test, referred to as residual risk, has been part of carrier screening for over 2 decades. Residual risks are calculated by subtracting the frequency of carriers of pathogenic variants detected by the test from the carrier frequency in a population, estimated from the incidence of the disease. Estimates of the incidence (and therefore carrier frequency) of many recessive disorders differ among different population groups and are inaccurate or unavailable for many genes on large carrier screening panels for most of the world's populations. The pathogenic variants detected by the test and their frequencies also vary across groups and over time as variants are newly discovered or reclassified, which requires today's residual carrier risks to be continually updated. Even when a residual carrier risk is derived using accurate data obtained in a particular group, it may not apply to many individuals in that group because of misattributed ancestry or unsuspected admixture. Missing or inaccurate data, the challenge of determining meaningful ancestry-specific risks and applying them appropriately, and a lack of evidence they impact management, suggest that patients be counseled that although carrier screening may miss a small fraction of carriers, residual risks with contemporary carrier screening are well below the risk posed by invasive prenatal diagnosis, even if one member of the couple is a carrier, and that efforts to provide precise residual carrier risks are unnecessary.

11.
Genet Med ; 23(9): 1673-1680, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34007000

RESUMO

PURPOSE: To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. METHODS: An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. RESULTS: In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. CONCLUSION: The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33857637

RESUMO

BACKGROUND & AIMS: Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing. METHODS: We performed a prospective multisite study of germline sequencing using a more than 80-gene next-generation sequencing platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: Of 361 patients, the median age was 57 years (SD, 12.4 y), 43.5% were female, 82% were white, and 38.2% had stage IV disease. PGVs were found in 15.5% (n = 56) of patients, including 44 in moderate- and high-penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC-specific gene panel. Only younger age at diagnosis was associated with the presence of PGVs (odds ratio, 1.99; 95% CI, 1.12-3.56). After a median follow-up period of 20.7 months, no differences in overall survival were seen between those with or without a PGV (P = .2). Eleven percent of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%). CONCLUSIONS: Universal multigene panel testing in CRC was associated with a modest, but significant, detection of heritable mutations over guideline-based testing. One in 10 patients had changes in their management based on test results. Uptake of cascade family testing was low, which is a concerning observation that warrants further study.

13.
Am J Hum Genet ; 108(4): 696-708, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743207

RESUMO

The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.


Assuntos
Processamento Alternativo/genética , Técnicas e Procedimentos Diagnósticos , Doença/genética , RNA/análise , Análise de Sequência de RNA , Incerteza , Estudos de Coortes , Simulação por Computador , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA/genética , Sítios de Splice de RNA/genética
16.
JAMA Oncol ; 7(2): 230-237, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33126242

RESUMO

Importance: Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing. Objective: To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT). Design, Setting, and Participants: This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age. Exposures: Germline sequencing using a greater than 80-gene next-generation sequencing platform. Main Outcomes and Measures: Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families. Results: A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT. Conclusions and Relevance: This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.

18.
Bioinformatics ; 36(22-23): 5448-5455, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33300982

RESUMO

MOTIVATION: When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental 'variant effect maps' that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation. RESULTS: Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation. AVAILABILITY AND IMPLEMENTATION: Source code available at: https://github.com/rothlab/mave-gene-prioritization. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Mutação de Sentido Incorreto , Proteínas
19.
JAMA Netw Open ; 3(10): e2019452, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026450

RESUMO

Importance: Both germline genetic testing and tumor DNA sequencing are increasingly used in cancer care. The indications for testing and utility of these 2 tests differ, and guidelines recommend that germline analysis follow tumor sequencing in certain patients to determine whether particular variants are of somatic or germline origin. Broad clinical experience with such follow-up testing has not yet been thoroughly described. Objective: To examine the yield and utility of germline testing following tumor DNA sequencing in a large, diverse patient population. Design, Setting, and Participants: A retrospective cohort study examined germline testing through a laboratory supporting multiple academic and community clinics. Participants included 2023 patients with cancer who received germline testing and previously underwent tumor DNA sequencing. These patients received germline testing between January 5, 2015, and January 31, 2020, although most (81% of patients) received testing between January 2, 2018, and January 31, 2020. Main Outcomes and Measures: The prevalence of pathogenic germline variants (PGVs) was calculated by gene, cancer type, and age at diagnosis. Potential actionability of these findings was determined based on current management guidelines, precision therapy labels, and clinical trial eligibility criteria. Patient records were reviewed to determine whether germline follow-up testing would have been recommended by current guidelines. Results: Among 2023 eligible patients, 1085 were female (53.6%), and the median age at cancer diagnosis was 56 (range, 0-92) years. Pathogenic germline variants were detected in 617 patients (30.5%; 95% CI, 28.5%-32.6%) and were prevalent across patient ages (1-85 years) and cancer types, including cancers known to be strongly associated with germline variance (eg, breast, colorectal) as well as others (eg, renal, lung, and bladder). Many patients (78%-82%) with PGVs met criteria for germline follow-up testing, and 8.1% of PGVs were missed by tumor sequencing. Among those with germline-positive findings, 69 patients (11.2%) had PGVs identified only after presenting with a second primary cancer that possibly could have been detected earlier or prevented given current gene-specific surveillance and risk-reduction recommendations. Conclusions and Relevance: The findings of this study suggest that germline analysis following tumor sequencing often produces findings that may impact patient care by influencing systemic therapy choices, surgical decisions, additional cancer screening, and genetic counseling in families. Current guidelines and tumor testing approaches appear to capture many, but not all, of these germline findings, reinforcing the utility of both expanded germline follow-up testing as well as germline analysis independent of tumor sequencing in appropriate patients.


Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Perfilação da Expressão Gênica/métodos , Testes Genéticos/estatística & dados numéricos , Células Germinativas/patologia , Neoplasias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
20.
Nat Med ; 26(9): 1392-1397, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32778825

RESUMO

Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)1-4. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.


Assuntos
Exoma/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Triagem Neonatal/métodos , Sequenciamento Completo do Exoma/métodos , Testes Genéticos , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/epidemiologia , Espectrometria de Massas em Tandem
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