Prenatal genomic microarray and sequencing in Canadian medical practice: towards consensus

Buchanan, Janet A.; Chitayat, David; Kolomietz, Elena; Lee, Hin C.; Scherer, Stephen W.; Speevak, Marsha D.; Sroka, Hana; Stavropoulos, Dimitri J.

doi:10.1136/jmedgenet-2015-103223

Cited by 6 publications

(3 citation statements)

References 10 publications

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“… 19 35 A 2014 Canadian microarray symposium reached consensus that for prenatal array, thresholds should be set at 500 kb for deletions and 1 Mb for duplications; CNVs of ‘ uncertain clinical significance’ that are smaller than these size limits should not be reported. 36 It was also agreed that variants of ‘ uncertain clinical significance’ exceeding these size thresholds should not be reported automatically; rather, such variants should only be reported if there is some published, but not necessarily conclusive, evidence that they may be pathogenic.…”

Section: Considerations For Technical Aspects and Reportingmentioning

confidence: 99%

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

et al. 2018

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BackgroundThe aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update.MethodsA multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017.Results and conclusionsRecommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9).

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Section: Considerations For Technical Aspects and Reportingmentioning

confidence: 99%

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

et al. 2018

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“…We classified this duplication as a VOUS. Because the repeated fragment was relatively small, that is, smaller than the threshold of 500kb for deletions and 1 Mb for duplications (Buchanan et al, 2015). This variant was likely to be benign.…”

Section: Fetuses With Nts Of 25-34 MMmentioning

confidence: 99%

Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype

Huang

et al. 2019

Molec Gen & Gen Med

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Background Submicroscopic chromosomal imbalance is associated with an increased nuchal translucency (NT). Most previous research has recommended the use of chromosomal microarray analysis (CMA) for prenatal diagnosis if the NT ≥ 3.5 mm. However, there is no current global consensus on the cutoff value for CMA. In this study, we aimed to discuss the fetuses with smaller increased NT which was between cutoff value of NT for karyotype analysis (NT of 2.5 mm in China) and the recommended cutoff value for CMA (NT of 3.5 mm) whether should be excluded from CMA test. Methods Singleton pregnant women (N = 192) who had undergone invasive procedures owing to an increased NT (NT ≥ 2.5 mm) were enrolled. Fetal cells were collected and subjected to single nucleotide polymorphism array and karyotype analyses simultaneously. Cases were excluded if the karyotype analysis indicated aneuploidy and apparent structural aberrations. Results Fourteen cases of aneuploidy and four cases of structural abnormalities were excluded. Of the remaining 174 cases, 119 fetuses had NTs of 2.5–3.4 mm, and 55 fetuses with NT ≥ 3.5 mm. Eleven copy number variants (CNVs) were identified. In fetuses with smaller NTs, six (6/119, 5.9%) variations were detected, including two (2/119, 1.6%) clinically significant CNVs (pathogenic or likely pathogenic CNV), one likely benign CNV, two variants unknown significance, and one incidental CNV. Five (5/55, 9.1%) variations were found in fetuses with NT ≥ 3.5 mm. Among these CNVs, three (3/55, 5.5%) cases had clinically significant CNVs, and two had likely benign CNV. There were no statistically significant differences in the incidence of all CNVs and clinically significant CNVs in the two groups (p > 0.05). Conclusion CMA improved the diagnostic yield of chromosomal aberrations for fetuses with NTs of 2.5–3.4 mm and apparently normal karyotype, regardless of whether other ultrasonic abnormalities were observed.

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“…In our center we do not report benign variants or VOUS in fetuses with normal ultrasound findings, but we report incidental findings, if the couple has indicated during counseling that this is their wish. The final issue is whether the use of CMA should be extended beyond specific indications and applied more generally; increasingly, centers are in fact replacing standard karyotyping with CMA for all invasive procedures. The rationale for offering CMA to all pregnant women is based on the fact that pathogenic CNVs are found in more than 1% of women with no previous risk factors, a higher rate than the classical 1/250 cut‐off for invasive testing.…”

Section: Initially Targeting Down Syndrome and Spina Bifidamentioning

confidence: 99%

A new comprehensive paradigm for prenatal diagnosis: seeing the forest through the trees

Borrell

2018

Ultrasound in Obstet & Gyne

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Prenatal genomic microarray and sequencing in Canadian medical practice: towards consensus

Cited by 6 publications

References 10 publications

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype

A new comprehensive paradigm for prenatal diagnosis: seeing the forest through the trees

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