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OBJECTIVE: 22q11.2 deletion syndrome (DS) is a serious condition with a range of features. The small microdeletion causing 22q11.2DS makes it technically challenging to detect using standard prenatal cfDNA screening. Here, we assess 22q11.2 microdeletion clinical performance by a prenatal cfDNA screen that incorporates fetal fraction (FF) amplification. METHODS: The study cohort consisted of patients who received Prequel (Myriad Genetics, Inc.), a prenatal cfDNA screening that incorporates FF amplification, and met additional eligibility criteria. Pregnancy outcomes were obtained via a routine process for continuous quality improvement. Samples with diagnostic testing results were used to calculate positive predictive value (PPV). RESULTS: 379,428 patients met study eligibility criteria, 76 of whom were screen-positive for a de novo 22q11.2 microdeletion. 22 (29.7%) had diagnostic testing results available, and all 22 cases were confirmed as true positives, for a PPV of 100% (95% CI 84.6%-100%). This performance was based on cases that ranged broadly across FF (5.9%-41.1%, mean 23.0%), body mass index (22.3-44.8, mean 29.9), and gestational age at testing (10.0w-34.6w, median 12.7w). Ultrasound findings in screen-positive pregnancies were consistent with those known to be associated with 22q11.2DS. CONCLUSION: 22q11.2 microdeletion screening that incorporates FF amplification demonstrated high PPV across both general and high-risk population cohorts.
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Ácidos Nucleicos Libres de Células , Síndrome de DiGeorge , Valor Predictivo de las Pruebas , Humanos , Femenino , Embarazo , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Ácidos Nucleicos Libres de Células/análisis , Ácidos Nucleicos Libres de Células/sangre , Adulto , Pruebas Prenatales no Invasivas/métodos , Pruebas Prenatales no Invasivas/estadística & datos numéricos , Estudios de Cohortes , Pruebas de Detección del Suero Materno/estadística & datos numéricos , Pruebas de Detección del Suero Materno/métodos , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/estadística & datos numéricosRESUMEN
Carrier screening tests reproductive couples for their risk of having children affected by serious monogenic conditions. Carrier screening has historically been offered for certain conditions in high-risk populations. However, more recent evidence has shown that offering carrier screening to all patients, regardless of their ethnicity, more effectively and equitably identifies at-risk couples. Coupled with technology that enables screening for a nearly unlimited number of conditions, this expanded carrier screening (ECS) approach is now supported by professional society guidelines. Despite recent recommendations by the American College of Medical Genetics and Genomics to screen all patients who are pregnant or considering pregnancy for 113 conditions, questions remain about what conditions should be included on a core ECS panel. Here, we briefly review the history of carrier screening and guidelines on criteria for panel design. We then suggest which of these criteria are most critical, as well as thresholds to identify which conditions meet these criteria. Based on these interpretations, we recommend a core panel of 64 conditions that would identify the vast majority of at-risk couples. Widespread adoption of a core panel such as this would result in a marked improvement in the number of patients currently receiving comprehensive carrier screening.
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Asesoramiento Genético , Pruebas Genéticas , Embarazo , Femenino , Niño , Humanos , Tamización de Portadores Genéticos , Diagnóstico Prenatal , EtnicidadRESUMEN
PURPOSE: The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) suggest carrier screening panel design criteria intended to ensure meaningful results. This study used a data-driven approach to interpret the criteria to identify guidelines-consistent panels. METHODS: Carrier frequencies in >460,000 individuals across 11 races/ethnicities were used to assess carrier frequency. Other criteria were interpreted on the basis of published data. A total of 176 conditions were then evaluated. Stringency thresholds were set as suggested by ACOG and/or ACMG or by evaluating conditions already recommended by ACOG and ACMG. RESULTS: Forty and 75 conditions had carrier frequencies of ≥1 in 100 and ≥1 in 200, respectively; 175 had a well-defined phenotype; and 165 met at least 1 severity criterion and had an onset early in life. Thirty-seven conditions met conservative thresholds, including a carrier frequency of ≥1 in 100, and 74 conditions met permissive thresholds, including a carrier frequency of ≥1 in 200; thus, both were identified as guidelines-consistent panels. CONCLUSION: Clear panel design criteria are needed to ensure quality and consistency among carrier screening panels. Evidence-based analyses of criteria resulted in the identification of guidelines-consistent panels of 37 and 74 conditions.
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Etnicidad , Pruebas Genéticas , Tamización de Portadores Genéticos/métodos , Pruebas Genéticas/métodos , Genómica , Humanos , InvestigaciónRESUMEN
PURPOSE: The percentage of a maternal cell-free DNA (cfDNA) sample that is fetal-derived (the fetal fraction; FF) is a key driver of the sensitivity and specificity of noninvasive prenatal screening (NIPS). On certain NIPS platforms, >20% of women with high body mass index (and >5% overall) receive a test failure due to low FF (<4%). METHODS: A scalable fetal fraction amplification (FFA) technology was analytically validated on 1264 samples undergoing whole-genome sequencing (WGS)-based NIPS. All samples were tested with and without FFA. RESULTS: Zero samples had FF < 4% when screened with FFA, whereas 1 in 25 of these same patients had FF < 4% without FFA. The average increase in FF was 3.9-fold for samples with low FF (2.3-fold overall) and 99.8% had higher FF with FFA. For all abnormalities screened on NIPS, z-scores increased 2.2-fold on average in positive samples and remained unchanged in negative samples, powering an increase in NIPS sensitivity and specificity. CONCLUSION: FFA transforms low-FF samples into high-FF samples. By combining FFA with WGS-based NIPS, a single round of NIPS can provide nearly all women with confident results about the broad range of potential fetal chromosomal abnormalities across the genome.
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Ácidos Nucleicos Libres de Células , Pruebas Prenatales no Invasivas , Aneuploidia , Ácidos Nucleicos Libres de Células/genética , Aberraciones Cromosómicas , Femenino , Feto , Humanos , Embarazo , Atención Prenatal , Diagnóstico PrenatalRESUMEN
PURPOSE: Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk. METHODS: For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data. RESULTS: Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve. CONCLUSION: Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.
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Etnicidad , Asesoramiento Genético , Etnicidad/genética , Tamización de Portadores Genéticos , Pruebas Genéticas , Humanos , AutoinformeRESUMEN
OBJECTIVE: Women with high body mass index (BMI) tend to have reduced fetal fraction (FF) during cell-free DNA-based noninvasive prenatal screening (NIPS), causing test failure rates up to 24.3% and prompting guidelines that recommend aneuploidy screening other than NIPS for patients with significant obesity. Because alternatives to NIPS are only preferable if they perform better, we compared the respective sensitivities at different BMI levels of traditional aneuploidy screening and a customized whole-genome sequencing NIPS. METHOD: The relationship between FF, aneuploidy, and BMI was quantified from 58 105 patients screened with a customized NIPS that does not fail samples because of low FF alone. Expected analytical sensitivity as a function of aneuploidy and BMI (eg, trisomy 18 sensitivity when BMI = 35) was determined by scaling the BMI- and aneuploidy-specific FF distribution by the FF- and aneuploidy-specific sensitivity calculated from empirically informed simulations. RESULTS: Across all classes of obesity and assuming zero FF-related test failures, analytical sensitivity for the investigated NIPS exceeded that of traditional aneuploidy screening for trisomies 13, 18, and 21. CONCLUSION: Relative to traditional aneuploidy screening, a customized NIPS with high accuracy at low FF and a low test-failure rate is a superior screening option for women with high BMI.
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Aneuploidia , Índice de Masa Corporal , Ácidos Nucleicos Libres de Células/sangre , Errores Diagnósticos/estadística & datos numéricos , Pruebas Prenatales no Invasivas/métodos , Secuenciación Completa del Genoma/métodos , Síndrome de Down/diagnóstico , Femenino , Feto , Humanos , Obesidad/complicaciones , Embarazo , Complicaciones del Embarazo , Sensibilidad y Especificidad , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 18/diagnósticoRESUMEN
This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY-NC-ND 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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PURPOSE: The American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of noncarriers, one criterion requires a per-condition carrier rate greater than 1 in 100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel design criteria on at-risk couple detection warrants data-driven evaluation. METHODS: Carrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation. RESULTS: Different interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11-81% fewer at-risk couples, and detect 36-79% fewer carriers than a 176-condition panel. If the carrier rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000. CONCLUSION: The 1-in-100 criterion limits at-risk couple detection and should be reconsidered.
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Tamización de Portadores Genéticos/métodos , Asesoramiento Genético/métodos , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas , Variaciones en el Número de Copia de ADN/genética , Femenino , Tamización de Portadores Genéticos/normas , Asesoramiento Genético/normas , Enfermedades Genéticas Congénitas/diagnóstico , Guías como Asunto , Heterocigoto , Humanos , Masculino , Mutación/genéticaRESUMEN
PURPOSE: Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. METHODS: Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. RESULTS: Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. CONCLUSION: ECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.
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Servicios de Planificación Familiar , Tamización de Portadores Genéticos , Adulto , Estudios de Cohortes , Femenino , Asesoramiento Genético , Humanos , Persona de Mediana Edad , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal , Encuestas y CuestionariosRESUMEN
PURPOSE: Medical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility. METHODS: Analytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants ("CF23"), sequencing all coding bases in CFTR ("NGS"), and sequencing with large copy-number variant (CNV) identification ("NGS + CNV"). Clinical utility was determined via self-reported actions of at-risk couples (ARCs). RESULTS: Analytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant. CONCLUSION: Modern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.
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Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Pruebas Genéticas/métodos , Adulto , Variaciones en el Número de Copia de ADN/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación INDEL/genética , Mutación/genética , Embarazo , Sensibilidad y EspecificidadRESUMEN
The original version of this Article contained an error in Figure 3. Specifically, the result "3 (67%) TOP" should read "2 (67%) TOP." This has now been corrected in both the PDF and HTML versions of the Article.
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PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.
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Tamización de Portadores Genéticos/métodos , Tamización de Portadores Genéticos/normas , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Genómica/métodos , Genómica/normas , Adhesión a Directriz , Humanos , Reproducibilidad de los ResultadosRESUMEN
Expanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes to determine reproductive risk. Data on the clinical utility of screening conditions beyond professional guidelines are scarce. Individuals underwent ECS for up to 110 genes. Five-hundred thirty-seven at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to participate in a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results. Sixty-four eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n = 28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. Twenty-nine percent (n = 13) were not planning to alter reproductive decisions. The remaining 9% (n = 4) of responses were unclear. Of 19 pregnant respondents, 42% (n = 8) elected PNDx, 11% (n = 2) planned amniocentesis but miscarried, and 47% (n = 9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. Two of 3 affected pregnancies were terminated. Disease severity was found to have significant association (p = 0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p = 0.284). Most ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.
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Tamización de Portadores Genéticos/métodos , Conducta Reproductiva/psicología , Esposos/psicología , Adaptación Psicológica , Toma de Decisiones , Femenino , Genes Recesivos , Humanos , Infertilidad/psicología , Masculino , Embarazo , Diagnóstico Prenatal/psicología , Estudios RetrospectivosRESUMEN
OBJECTIVE: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences. METHODS: A total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival. RESULTS: Smith-Lemli-Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise. CONCLUSION: Smith-Lemli-Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
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Tamización de Portadores Genéticos , Síndrome de Smith-Lemli-Opitz/diagnóstico , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/mortalidad , Femenino , Mortalidad Fetal , Frecuencia de los Genes , Tamización de Portadores Genéticos/métodos , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Polimorfismo de Nucleótido Simple , Embarazo , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/estadística & datos numéricos , Estudios Retrospectivos , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies. METHODS: Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. RESULTS: The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. CONCLUSION: The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
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Análisis Mutacional de ADN/métodos , Feto/química , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Límite de Detección , Análisis por Micromatrices/métodos , Polimorfismo de Nucleótido Simple , Diagnóstico Prenatal/métodos , ADN/análisis , Femenino , Feto/metabolismo , Pruebas Genéticas , Genoma Humano , Humanos , Masculino , Embarazo , Sensibilidad y EspecificidadRESUMEN
PURPOSE OF REVIEW: Expanded carrier screening, which detects carriers for a large number of autosomal recessive and X-linked diseases, is increasing in clinical utilization. A recent joint statement from multiple professional societies, in addition to a growing literature base, offers perspective on rationale, decision points, and reasonable methods of implementation. RECENT FINDINGS: Current literature addresses three areas: pre- and posttest education, including optimal use of formal genetic counseling, and differing characteristics of laboratory tests. Surveys of obstetricians and genetics providers also offer insight into optimal practice methods. SUMMARY: We review the carrier screening process in chronological sequence - pretest, test selection, and posttest results disclosure - and points to be considered, recommending possible practice protocols based on available literature and our combined laboratory and clinical practice experience.
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Asesoramiento Genético , Pruebas Genéticas/métodos , Heterocigoto , Asesoramiento Genético/ética , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
IMPORTANCE: Screening for carrier status of a limited number of single-gene conditions is the current standard of prenatal care. Methods have become available allowing rapid expanded carrier screening for a substantial number of conditions. OBJECTIVES: To quantify the modeled risk of recessive conditions identifiable by an expanded carrier screening panel in individuals of diverse racial and ethnic backgrounds and to compare the results with those from current screening recommendations. DESIGN, SETTING, AND PARTICIPANTS: Retrospective modeling analysis of results between January 1, 2012, and July 15, 2015, from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. EXPOSURES: Individuals were tested for carrier status for up to 94 severe or profound conditions. MAIN OUTCOMES AND MEASURES: Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories; there were 11 categories with >5000 samples) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both. RESULTS: The study included 346,790 individuals. Among major US racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100,000 (95% CI, 82.4-108.3 per 100,000) for Hispanic couples to 392.2 per 100,000 (95% CI, 366.3-420.2 per 100,000) for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines (Mann-Whitney P < .001). For Northern European couples, the 2 professional guidelines-based screening panels modeled 55.2 hypothetical fetuses affected per 100,000 (95% CI, 51.3-59.3 per 100,000) and the expanded carrier screening modeled 159.2 fetuses per 100,000 (95% CI, 150.4-168.6 per 100,000). Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6% (95% CI, 4%-8%) of hypothetical fetuses affected for East Asian couples to 87% (95% CI, 84%-90%) for African or African American couples. CONCLUSIONS AND RELEVANCE: In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies. Prospective studies comparing current standard-of-care carrier screening with expanded carrier screening in at-risk populations are warranted before expanded screening is adopted.
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Enfermedades Fetales/genética , Tamización de Portadores Genéticos/métodos , Enfermedades Genéticas Congénitas/diagnóstico , Pueblo Asiatico/genética , Población Negra/genética , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Genéticas Congénitas/etnología , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Técnicas de Genotipaje/métodos , Heterocigoto , Hispánicos o Latinos/genética , Homocigoto , Humanos , Indígenas Norteamericanos/genética , Judíos/genética , Masculino , Estudios Retrospectivos , Estadísticas no Paramétricas , Estados Unidos/etnología , Población Blanca/genéticaRESUMEN
Genetic disease is the leading cause of infant death in the United States, accounting for approximately 20% of annual infant mortality. Advances in genomic medicine and technological platforms have made possible low cost, pan-ethnic expanded genetic screening that enables obstetric care providers to offer screening for over 100 recessive genetic diseases. However, the rapid integration of genomic medicine into routine obstetric practice has raised some concerns about the practical implementation of such testing. These changing trends in carrier screening, along with concerns and potential solutions, will be addressed.
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Tamización de Portadores Genéticos , Pruebas Genéticas/tendencias , Diagnóstico Prenatal/tendencias , Asesoramiento Genético , Humanos , Consentimiento Informado , Diagnóstico Prenatal/psicología , Estereotipo , Estados UnidosRESUMEN
IMPORTANCE: Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignancies may explain results that are discordant with the fetal karyotype and improve maternal clinical care. OBJECTIVE: To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. DESIGN, SETTING, AND PARTICIPANTS: Case series identified from 125,426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation. EXPOSURES: NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). MAIN OUTCOMES AND MEASURES: Detailed genome-wide bioinformatics analysis was performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort. RESULTS: From a cohort of 125,426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95% CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. CONCLUSIONS AND RELEVANCE: In this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research.