Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening

Haque, Imran S.; Lazarin, Gabriel A.; Kang, Hyunseok P.; Evans, E. Edward; Goldberg, James D.; Wapner, Ronald J.

doi:10.1097/01.ogx.0000511254.16194.96

Cited by 49 publications

(71 citation statements)

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“…Because of the increasing quality and decreasing cost of genomic technologies, it is now possible to perform pan-ethnic carrier screening for many conditions simultaneously [referred to as expanded carrier screening (ECS) 2 ]. Our previous study of carrier rates in 346 790 patients showed that an ECS panel was expected to identify more pregnancies at risk for serious conditions than ethnic-based panels spanning far fewer genes (4 ), and the American College of Obstetricians and Gynecologists recently recognized ECS as an acceptable strategy for preconception and prenatal carrier screening (5 ). To the extent that these guidelines increase ECS usage, they will have a large clinical impact because it has recently been shown in clinical-utility studies that approximately 80% of couples found to be at risk for severe conditions pursue alternative reproductive options (6,7 ).…”

confidence: 99%

“…MFDR was a modeled estimate of the probability that a pregnancy was affected by a condition on the panel (it could be summed across diseases to yield an aggregate MFDR of the panel), whereas an ARC, as used herein, was a couple identified empirically as being at high risk for an affected child. Reported MFDR numbers were calculated as described previously (4,10 ) only patients receiving routine carrier screening and, therefore, excluded those with known family history or infertility. By contrast, the reported couple and ARC counts are raw counts, not necessarily representative of the general US population because of the over-representation of high-risk ethnic groups, infertility patients, and patients with family history of disease.…”

Section: Patient Cohortmentioning

confidence: 99%

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Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Hogan¹,

Vysotskaia²,

Beauchamp³

et al. 2018

Clinical Chemistry

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BACKGROUND By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. RESULTS Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS Validated high-fidelity identification of different variant types—especially for diseases with complicated molecular genetics—maximizes at-risk couple detection.

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confidence: 99%

Section: Patient Cohortmentioning

confidence: 99%

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Hogan¹,

Vysotskaia²,

Beauchamp³

et al. 2018

Clinical Chemistry

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“…Other programs in the Middle East have had mixed success. Expanded carrier screening panels are now available for a large number of autosomal recessive genetic conditions [57]. However, in Western countries with mixed ethnic groups it may be more difficult to show utility in universal screening.…”

Section: Clinical Implications Of Identifying Thalassemia Traitmentioning

confidence: 99%

Distinguishing iron deficiency anaemia from thalassemia trait in clinical obstetric practice

Akers¹,

Howard²,

Ford³

2018

J Pregnancy Reprod

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Anaemia in pregnancy is common, occurring in approximately 38% of pregnancies. Iron deficiency anaemia (IDA) accounts for most cases (55% -70%) depending on the population being studied. However, both alpha and beta thalassemia trait cause microcytic, hypochromic anaemia and are commonly misdiagnosed as IDA. Thalassemia trait (or minor) should be considered when there is a microcytic anaemia that is not improving with iron therapy or when anaemia predates the pregnancy, especially in a patient from a high risk ethnic group. Also, certain features on the complete blood count (CBC) indices can suggest thalassemia trait such as microcytosis out of proportion to the anaemia along with a raised RBC count. A diagnosis of beta thalassemia trait can be made by the detection of an elevated Hb A2. A diagnosis of alpha thalassemia trait can be made by demonstrating Hemoglobin H bodies on the peripheral blood smear using special stains. In some thalassemia patients with equivocal phenotypic results, genetic testing for specific thalassemia mutations may be required. Identification of women with thalassemia trait is important for genetic counselling as well as avoiding unnecessary iron replacement therapy.

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“…A panel test for four severe childhood conditions was developed in a specific Dutch founder population [4] and panel tests designed for Jewish populations now include more than 10 disorders. Commercial providers have started offering panel tests for more than 100 diseases [5]. Expanded carrier tests offer the advantage that a larger proportion of potentially affected fetuses can be recognized [5,6].…”

Section: Preconception Carrier Screeningmentioning

confidence: 99%

“…Commercial providers have started offering panel tests for more than 100 diseases [5]. Expanded carrier tests offer the advantage that a larger proportion of potentially affected fetuses can be recognized [5,6]. A disadvantage, however, is that the person tested does not know the conditions that they can be tested for; therefore, the perceived sense of urgency may be limited and informed decision-making more difficult [7,8].…”

Section: Preconception Carrier Screeningmentioning

confidence: 99%

Responsible Implementation of Expanded Screening Programs for Genetic Diseases at the Beginning of Life

Cornel¹

2018

obm genet

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Abstract:Technology makes it possible to expand many of the current screening programs. Initiatives for preconception screening of carrier status of recessive diseases, prenatal screening of aneuploidies and neonatal screening were initially undertaken by targeting one or at most, a few, conditions. Tandem mass spectrometry and genomic technologies, such as sequencing and panel testing, make it possible to increase the scope of these programs to include more disorders or markers. While inclusion of a larger number of conditions with similar characteristics may lead to greater success in the goal of screening, the inclusion of nonsimilar conditions raises new questions. Informed decision-making requires adequate and relevant information, which may be a challenge if many more conditions are added, especially for non-similar conditions. The goals of offering health benefits and greater reproductive choice may become blurred; thus, clear communication of the aims of screening is imperative. Screening for more conditions risks increasing the number of false positives. Evaluation of the pros and cons of screening programs, including the costeffectiveness, is needed to ascertain the potential of expanded screening. Targeted analysis OBM Genetics 2018; 2(1), doi:10.21926/obm.genet.1801013Page 2/7 based on careful evaluation of these pros and cons combined with the availability of new technologies represents an important opportunity to devise expanded screening programs.

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Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening

Cited by 49 publications

References 0 publications

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Distinguishing iron deficiency anaemia from thalassemia trait in clinical obstetric practice

Responsible Implementation of Expanded Screening Programs for Genetic Diseases at the Beginning of Life

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