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Sylvie Langlois,
Jo-Ann Brock,
R Douglas Wilson,
François Audibert,
June Carroll,
Lola Cartier,
Alain Gagnon,
Jo-Ann Johnson,
William Macdonald,
Lynn Murphy-Kaulbeck,
Nanette Okun,
Melanie Pastuck,
Vyta Senikas
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ABSTRACT: Objective: To provide a review of published studies on the use of cell-free fetal DNA in maternal plasma for the non-invasive diagnosis of Down syndrome, trisomy 18, and trisomy 13. Evidence: PubMed was searched for articles published between 2006 and October 2012, using appropriate key words (e.g., non-invasive prenatal diagnosis, Down syndrome, cell-free fetal DNA, aneuploidy screening). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to October 31, 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The studies reviewed were classified according to criteria described by the Canadian Task Force on Preventive Health Care, and the recommendations for practice were ranked according to this classification (Table 1). Recommendations 1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A) 2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A) 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A).
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 02/2013; 35(2):177-81.
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ABSTRACT: [Bonnet et al. (2010); J Med Genet 47: 377-384] recently suggested a 4q21 microdeletion syndrome with several common features, including severe intellectual disability, lack of speech, hypotonia, significant growth restriction, and distinctive facial features. Overlap of the deleted regions of 13 patients, including a patient we previously reported, delineates a critical region, with PRKG2 and RASGEF1B emerging as candidate genes. Here we provide a detailed clinical report and photographic life history of our previously reported patient. Previous case reports of this new syndrome have not described the prognosis or natural history of these patients. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 08/2012; 158A(10):2606-9. · 2.39 Impact Factor
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Lola Cartier,
Lynn Murphy-Kaulbeck,
R Douglas Wilson,
François Audibert,
Jo-Ann Brock,
June Carroll,
Alain Gagnon,
Jo-Ann Johnson, Sylvie Langlois,
Nanette Okun,
Melanie Pastuck
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ABSTRACT: This document has been developed to aid clinicians in counselling patients about prenatal screening and to provide assistance in counselling about both positive and negative screening results.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 05/2012; 34(5):489-93.
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ABSTRACT: To provide the physician with an overview of common genetic conditions that should be considered during a women's annual gynaecological assessment to determine the patient's risk or to initiate specific testing or referral to another subspecialty service, depending on personal or family history.
This genetic information can be used for patient education and possible disease and/or mutation screening or diagnosis. Outcomes: The use of this genetic information may allow improved risk-benefit assessment and management at the annual gynaecological examination.
Studies published in English up to and including May 2010 were retrieved through searches of PubMed and the Cochrane Library, using appropriate controlled vocabulary (gynaecological diagnosis, genetic inheritance) and key words (genetic risk, genetic mutation, inheritance, family history, uterus, ovary, endometrial, vagina, colon, gastric, renal, breast, cardiac, thrombophilia, diabetes, epilepsy, leiomyomata uteri). Other literature sources were identified through searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The levels of evidence are not adequate for evidence-based recommendations to be made.
This committee opinion will enhance the use of new genetic knowledge and its application to the annual gynaecological care of women. Risk management and diagnostic opportunities for genetic gynaecological conditions will be improved. A more complete understanding of genetic conditions may increase anxiety and psychological stress for women and their families.
Society of Obstetricians and Gynaecologists of Canada.
The levels of evidence are not adequate for evidence-based recommendations to be made.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 03/2012; 34(3):276-84.
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ABSTRACT: To summarize for obstetrical care providers the current literature on array genomic hybridization in prenatal diagnosis and to outline the recommendations of the Canadian College of Medical Geneticists regarding the use of this new technology with respect to prenatal diagnosis.
PubMed and Medline were searched for articles published in English between 2004 and 2010, using the key words DNA QF-PCR, quantitative fluorescent polymerase chain reaction, fetal chromosomal abnormalities, prenatal diagnosis, array genomic hybridization, fetal structural anomalies, and copy number variants. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis, and articles were incorporated in the guideline to September 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).
1. Array genomic hybridization is not recommended in pregnancies at low risk for a structural chromosomal abnormality; for example, advanced maternal age, positive maternal serum screen, previous trisomy, or the presence of "soft markers" on fetal ultrasound. (III-D) 2. Array genomic hybridization may be an appropriate diagnostic test in cases with fetal structural abnormalities detected on ultrasound or fetal magnetic resonance imaging; it could be done in lieu of a karyotype if rapid aneuploidy screening is negative and an appropriate turnaround time for results is assured. (II-2A) 3. Any pregnant woman who qualifies for microarray genomic hybridization testing should be seen in consultation by a medical geneticist before testing so that the benefits, limitations, and possible outcomes of the analysis can be discussed in detail. The difficulties of interpreting some copy number variants should also be discussed. This will allow couples to make an informed decision about whether or not they wish to pursue such prenatal testing. (III-A).
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 12/2011; 33(12):1256-9.
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ABSTRACT: To provide Canadian health care providers with current information on the use of quantitative fluorescent polymerase chain reaction (QF-PCR) or equivalent technology in the prenatal diagnosis of fetal chromosomal abnormalities.
Over the last few decades, prenatal diagnosis of fetal chromosomal abnormalities has relied on conventional cytogenetic analysis of cultured amniocytes, chorionic villi, or fetal blood. In the last few years, the clinical validity of a newer technique, QF-PCR, to detect the common aneuploidies has been reported by a number of investigators. This technique has the advantage of providing rapid results for the diagnosis or exclusion of aneuploidy in chromosomes 13, 18, 21, X or Y. It is now possible to choose standard chromosome analysis or QF-PCR for the prenatal diagnosis of chromosomal abnormalities, or to perform both tests, depending on the clinical indication for testing. This document reviews the clinical utility of QF-PCR and makes recommendations for its use in the care of Canadian patients.
Medline and PubMed were searched for articles published in English between January 2000 and December 2010 that presented data on the use of QF-PCR versus standard cytogenetic analysis of prenatal samples. A second search was done to identify publications in English that provided results of cytogenetic analysis performed on prenatal samples for women at an increased risk of fetal aneuploidy because of maternal age, abnormal prenatal screening results, or fetal soft ultrasound markers suggestive of an increased risk of aneuploidy. Publications were included if they provided detailed information on the abnormalities detected, regardless of whether or not rapid aneuploidy screening was undertaken. Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).
This guideline promotes the use of a rapid aneuploidy DNA test for women at increased risk of having a pregnancy affected by a common aneuploidy. This will have the benefit of providing rapid and accurate results to women at increased risk of fetal Down syndrome, trisomy 13, trisomy 18, sex chromosome aneuploidy or triploidy. It will also promote better use of laboratory resources and reduce the cost of prenatal diagnosis. However, a small percentage of pregnancies with a potentially clinically significant chromosomal abnormality will remain undetected by QF-PCR but detectable by conventional cytogenetics. Recommendations 1. QF-PCR is a reliable method to detect trisomies and should replace conventional cytogenetic analysis whenever prenatal testing is performed solely because of an increased risk of aneuploidy in chromosomes 13, 18, 21, X or Y. As with all tests, pretest counselling should include a discussion of the benefits and limitations of the test. In the initial period of use, education for health care providers will be required. (II-2A) 2. Both conventional cytogenetics and QF-PCR should be performed in all cases of prenatal diagnosis referred for a fetal ultrasound abnormality (including an increased nuchal translucency measurement > 3.5 mm) or a familial chromosomal rearrangement. (II-2A) 3. Cytogenetic follow-up of QF-PCR findings of trisomy 13 and 21 is recommended to rule out inherited Robertsonian translocations. However, the decision to set up a back-up culture for all cases that would allow for traditional cytogenetic testing if indicated by additional clinical or laboratory information should be made by each centre offering the testing according to the local clinical and laboratory experience and resources. (III-A) 4. Other technologies for the rapid detection of aneuploidy may replace QF-PCR if they offer a similar or improved performance for the detection of trisomy 13, 18, 21, and sex chromosome aneuploidy. (III-A).
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 09/2011; 33(9):955-60.
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ABSTRACT: To develop a Canadian consensus document on maternal screening for fetal aneuploidy (e.g., Down syndrome and trisomy 18) in singleton pregnancies.
Pregnancy screening for fetal aneuploidy started in the mid 1960s, using maternal age as the screening test. New developments in maternal serum and ultrasound screening have made it possible to offer all pregnant patients a non-invasive screening test to assess their risk of having a fetus with aneuploidy to determine whether invasive prenatal diagnostic testing is necessary. This document reviews the options available for non-invasive screening and makes recommendations for Canadian patients and health care workers.
To offer non-invasive screening for fetal aneuploidy (trisomy 13, 18, 21) to all pregnant women. Invasive prenatal diagnosis would be offered to women who screen above a set risk cut-off level on non-invasive screening or to pregnant women whose personal, obstetrical, or family history places them at increased risk. Currently available non-invasive screening options include maternal age combined with one of the following: (1) first trimester screening (nuchal translucency, maternal age, and maternal serum biochemical markers), (2) second trimester serum screening (maternal age and maternal serum biochemical markers), or (3) 2-step integrated screening, which includes first and second trimester serum screening with or without nuchal translucency (integrated prenatal screen, serum integrated prenatal screening, contingent, and sequential). These options are reviewed, and recommendations are made.
Studies published between 1982 and 2009 were retrieved through searches of PubMed or Medline and CINAHL and the Cochrane Library, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline.
The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.
This guideline is intended to reduce the number of prenatal invasive procedures done when maternal age is the only indication. This will have the benefit of reducing the numbers of normal pregnancies lost because of complications of invasive procedures. Any screening test has an inherent false-positive rate, which may result in undue anxiety. It is not possible at this time to undertake a detailed cost-benefit analysis of the implementation of this guideline, since this would require health surveillance and research and health resources not presently available; however, these factors need to be evaluated in a prospective approach by provincial and territorial initiatives. RECOMMENDATIONS 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies in addition to a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A) 2. Counselling must be non-directive and must respect a woman's right to accept or decline any or all of the testing or options offered at any point in the process. (III-A) 3. Maternal age alone is a poor minimum standard for prenatal screening for aneuploidy, and it should not be used a basis for recommending invasive testing when non-invasive prenatal screening for aneuploidy is available. (II-2A) 4. Invasive prenatal diagnosis for cytogenetic analysis should not be performed without multiple marker screening results except for women who are at increased risk of fetal aneuploidy (a) because of ultrasound findings, (b) because the pregnancy was conceived by in vitro fertilization with intracytoplasmic sperm injection, or (c) because the woman or her partner has a history of a previous child or fetus with a chromosomal abnormality or is a carrier of a chromosome rearrangement that increases the risk of having a fetus with a chromosomal abnormality. (II-2E) 5. At minimum, any prenatal screen offered to Canadian women who present for care in the first trimester should have a detection rate of 75% with no more than a 3% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 6. The minimum standard for women presenting in the second trimester should be a screen that has a detection rate of 75% with no more than a 5% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 7. First trimester nuchal translucency should be interpreted for risk assessment only when measured by sonographers or sonologists trained and accredited for this service and when there is ongoing quality assurance (II-2A), and it should not be offered as a screen without biochemical markers in singleton pregnancies. (I-E) 8. Evaluation of the fetal nasal bone in the first trimester should not be incorporated as a screen unless it is performed by sonographers or sonologists trained and accredited for this service and there is ongoing quality assurance. (II-2E) 9. For women who undertake first trimester screening, second trimester serum alpha fetoprotein screening and/or ultrasound examination is recommended to screen for open neural tube defects. (II-1A) 10. Timely referral and access is critical for women and should be facilitated to ensure women are able to undergo the type of screening test they have chosen as first trimester screening. The first steps of integrated screening (with or without nuchal translucency), contingent, or sequential screening are performed in an early and relatively narrow time window. (II-1A) 11. Ultrasound dating should be performed if menstrual or conception dating is unreliable. For any abnormal serum screen calculated on the basis of menstrual dating, an ultrasound should be done to confirm gestational age. (II-1A) 12. The presence or absence of soft markers or anomalies in the 18- to 20-week ultrasound can be used to modify the a priori risk of aneuploidy established by age or prior screening. (II-2B) 13. Information such as gestational dating, maternal weight, ethnicity, insulin-dependent diabetes mellitus, and use of assisted reproduction technologies should be provided to the laboratory to improve accuracy of testing. (II-2A) 14. Health care providers should be aware of the screening modalities available in their province or territory. (III-B) 15. A reliable system needs to be in place ensuring timely reporting of results. (III-C) 16. Screening programs should be implemented with resources that support audited screening and diagnostic laboratory services, ultrasound, genetic counselling services, patient and health care provider education, and high quality diagnostic testing, as well as resources for administration, annual clinical audit, and data management. In addition, there must be the flexibility and funding to adjust the program to new technology and protocols. (II-3B).
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 07/2011; 33(7):736-50.
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Tracy Tucker,
Alexandre Montpetit,
David Chai,
Susanna Chan,
Sébastien Chénier,
Bradley P Coe,
Allen Delaney,
Patrice Eydoux,
Wan L Lam, Sylvie Langlois,
Emmanuelle Lemyre,
Marco Marra,
Hong Qian,
Guy A Rouleau,
David Vincent,
Jacques L Michaud,
Jan M Friedman
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ABSTRACT: Clinical laboratories are adopting array genomic hybridization as a standard clinical test. A number of whole genome array genomic hybridization platforms are available, but little is known about their comparative performance in a clinical context.
We studied 30 children with idiopathic MR and both unaffected parents of each child using Affymetrix 500 K GeneChip SNP arrays, Agilent Human Genome 244 K oligonucleotide arrays and NimbleGen 385 K Whole-Genome oligonucleotide arrays. We also determined whether CNVs called on these platforms were detected by Illumina Hap550 beadchips or SMRT 32 K BAC whole genome tiling arrays and tested 15 of the 30 trios on Affymetrix 6.0 SNP arrays.
The Affymetrix 500 K, Agilent and NimbleGen platforms identified 3061 autosomal and 117 X chromosomal CNVs in the 30 trios. 147 of these CNVs appeared to be de novo, but only 34 (22%) were found on more than one platform. Performing genotype-phenotype correlations, we identified 7 most likely pathogenic and 2 possibly pathogenic CNVs for MR. All 9 of these putatively pathogenic CNVs were detected by the Affymetrix 500 K, Agilent, NimbleGen and the Illumina arrays, and 5 were found by the SMRT BAC array. Both putatively pathogenic CNVs identified in the 15 trios tested with the Affymetrix 6.0 were identified by this platform.
Our findings demonstrate that different results are obtained with different platforms and illustrate the trade-off that exists between sensitivity and specificity. The large number of apparently false positive CNV calls on each of the platforms supports the need for validating clinically important findings with a different technology.
BMC Medical Genomics 03/2011; 4:25. · 3.69 Impact Factor
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R Douglas Wilson,
François Audibert,
Jo-Ann Brock,
Lola Cartier,
Valerie A Désilets,
Alain Gagnon,
Jo-Ann Johnson, Sylvie Langlois,
Lynn Murphy-Kaulbeck,
Nanette Okun,
Melanie Pastuck
[show abstract]
[hide abstract]
ABSTRACT: To give health care providers information about the genetic information that can be used as part of health surveillance for women undergoing a pre-conception evaluation for genetic risk assessment and possible genetic screening or testing.
This genetic information can be used for patient education and possible prenatal testing.
The use of this genetic information may allow improved risk-benefit assessment for pre-conception counselling for individual patients and their families.
PubMed or Medline and the Cochrane Database were searched in November 2009, using appropriate key words (pre-conception, genetic disease, maternal, family history, genetic health risk, genetic health surveillance, prenatal screening, prenatal diagnosis, birth defects, and teratogen). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies.
The benefits for the patient and her family include understanding of possible genetic risk and enhanced pregnancy outcomes. The harm includes increased anxiety or psychological stress associated with the possibility of identifying genetic risks.
The evidence obtained was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS AND SUMMARY STATEMENTS: A review of the current literature does not provide enough information for this committee opinion to present evidence-based recommendations.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 01/2011; 33(1):57-64.
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ABSTRACT: With a growing understanding of genetic disorders in the scientific and lay literature, it is becoming increasingly important to consider risk factors based on family history and ethnicity for identifying individuals for whom genetic testing is indicated and will be most beneficial. A pedigree helps to identify patients and families who have an increased risk for genetic disorders, to optimize counselling, screening, and diagnostic testing, with the goal of disease prevention or early diagnosis and management of the disease. Information should be updated periodically as new information regarding family history is acquired. This review was designed to provide a rationale for and an approach to obtaining a three-generation pedigree for patients who are seen as new assessments or those under ongoing care by primary care or specialist physicians, as well to summarize some resources available for constructing a useful pedigree.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 07/2010; 32(7):663-72.
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ABSTRACT: Russell-Silver syndrome (RSS) is a heterogeneous disorder associated with pre- and post-natal growth restriction and relative macrocephaly. Involvement of imprinted genes on both chromosome 7 and 11p15.5 has been reported. To further characterize the role of epimutations in RSS we evaluated the methylation status at both 11p15.5 imprinting control regions (ICRs): ICR1 associated with H19/IGF2 expression and ICR2 (KvDMR1) associated with CDKN1C expression in a series of 35 patients with RSS. We also evaluated methylation at the promoter regions of other imprinted genes involved in growth such as PLAGL1 (6q24), GCE (7q21), and PEG10 (7q21) in this series of 35 patients with RSS. Thirteen of the 35 patient samples, but none of 22 controls, showed methylation levels at ICR1 that were more than 2 SD below the mean for controls. Three RSS patients were highly methylated at the SCGE promoter, all of which were diagnosed with upd(7)mat. To identify further potential global methylation changes in RSS patients, a subset of 22 patients were evaluated at 1505 CpG sites by the Illumina GoldenGate methylation array. Among the few CpG sites displaying a significant difference between RSS patients and controls, was a CpG associated with the H19 promoter. No other sites associated with known imprinted genes were identified as abnormally methylated in RSS patients by this approach. While the association of hypomethylation of the H19/IGF2 ICR1 is clear, the continuous distribution of methylation values among the patients and controls complicates the establishment of clear cut-offs for clinical diagnosis.
American Journal of Medical Genetics Part A 02/2010; 152A(2):347-55. · 2.39 Impact Factor
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ABSTRACT: Prenatally diagnosed confined placental trisomy is associated with increased risk for intrauterine growth restriction (IUGR) and preeclampsia. However, it is unclear how often this might underlie pregnancy complications. Our objective was to evaluate the frequency and distribution of trisomic cells in placentae ascertained for IUGR and/or preeclampsia.
Comparative genomic hybridization was applied to two uncultured biopsies from each of 61 placentae referred with maternal preeclampsia and/or IUGR, 11 cases with elevated maternal serum hCG and/or AFP but no IUGR or preeclampsia, and 85 control placentae.
Trisomy was observed in four placentae among the IUGR group (N = 43) but in no case of preeclampsia in the absence of IUGR (N = 18). Trisomy was observed in 1 of the 11 cases ascertained for abnormal maternal serum screen. Each of these five cases was mosaic and not all sampled sites showed the presence of trisomy. None of the 84 control placentas showed mosaic trisomy, although 1 case of nonmosaic 47,XXX was identified in this group.
In cases in which diagnosis of the cause of IUGR may provide some benefit, testing should be performed using uncultured cells from multiple placental biopsies for the accurate diagnosis of trisomy mosaicism.
Prenatal Diagnosis 11/2009; 30(1):1-8. · 2.11 Impact Factor
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Jm Friedman,
Shelin Adam,
Laura Arbour,
Linlea Armstrong,
Agnes Baross,
Patricia Birch,
Cornelius Boerkoel,
Susanna Chan,
David Chai,
Allen D Delaney, [......],
Jacques L Michaud,
Barbara C McGillivray,
Millan S Patel,
Hong Qian,
Guy A Rouleau,
Margot I Van Allen,
Siu-Li Yong,
Farah R Zahir,
Patrice Eydoux,
Marco A Marra
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ABSTRACT: Array genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.
We performed 500 K Affymetrix GeneChip array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.
Affymetrix GeneChip 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.
BMC Genomics 11/2009; 10:526. · 4.07 Impact Factor
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Alain Gagnon,
R Wilson,
Victoria Allen,
François Audibert,
Claire Blight,
Jo-Ann Brock,
Valerie Désilets,
Jo-Ann Johnson, Sylvie Langlois,
Lynn Murphy-Kaulbeck,
Philip Wyatt
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ABSTRACT: Objectif : Offrir des renseignements aux conseillers génétiques, aux sages-femmes, aux infirmières et aux médecins qui prennent part aux soins prénatals offerts aux femmes qui sont aux prises avec des anomalies congénitales structurelles, isolées ou multiples, diagnostiquées pendant la période prénatale. Issues : Offrir de meilleurs services de counseling aux femmes et aux familles qui sont aux prises avec un diagnostic d'anomalie structurelle foetale. Résultats : La littérature publiée a été identifiée par l'intermédiaire de recherches menées dans PubMed ou Medline, CINAHL et la Cochrane Library, au moyen d'un vocabulaire contrôlé approprié (p. ex. anomalies congénitales structurelles, diagnostic d'anomalies congénitales établi au moyen d'une échographie prénatale, résultats d'un dépistage effractif et diagnostic des syndromes génétiques; les marqueurs faibles de l'aneuploïdie n'ont pas été inclus aux fins de cette recherche) et de mots clés. Les résultats ont été restreints aux analyses systématiques, aux essais comparatifs randomisés / essais cliniques comparatifs et aux études observationnelles. Aucune restriction quant à la date ou à la langue n'a été mise en oeuvre. Les recherches ont été régulièrement mises à jour et les données publiées entre 1985 et 2008 ont été intégrées à la directive clinique. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques et auprès de sociétés de spécialité médicale nationales et internationales. Valeurs : Les résultats obtenus ont été évalués par le comité sur la génétique de la Société des obstétriciens et gynécologues du Canada (SOGC). Les recommandations ont été quantifiées au moyen des lignes directrices sur l'évaluation des résultats élaborées par le Groupe d'étude canadien sur les soins de santé préventifs. Avantages, désavantages et coûts : La constatation d'anomalies foetales isolées ou multiples au moment de l'examen échographique prénatal engendre toujours du stress pour les femmes et leur famille. Bien qu'une proportion de ces anomalies puisse être expliquée par la présence d'anomalies chromosomiques (aneuploïdie, translocation déséquilibrée, délétions ou duplications), d'autres anomalies peuvent représenter des syndromes identifiables reposant sur une toute autre base génétique (microdélétion ou hérédité dominante, récessive ou liée au chromosome X autosomique). L'offre de renseignements précis et de services de counseling génétique génésique pertinents à ces femmes et à leur famille leur permettra de prendre des décisions éclairées. Il ne s'agit pas d'une tâche facile, puisque les renseignements disponibles pendant la période prénatale sont limités. Le présent document n'offre pas une description exhaustive de chaque syndrome, mais plutôt un cadre de référence. Aucune analyse coûts-avantages n'est offerte. Recommandations 1. Lorsqu'une anomalie structurelle foetale est identifiée, la patiente enceinte devrait se voir offrir une consultation en temps opportun auprès d'un conseiller formé en ce qui concerne la génétique, ainsi qu'auprès d'un spécialiste en médecine foeto-maternelle et/ou d'un généticien médical. Le counseling offert se doit d'être impartial et de respecter le choix, la culture, la religion et les convictions de la patiente. (III-A) 2. Les patientes devraient être avisées que la tenue d'une échographie prénatale entre la 18e et la 20e semaine de gestation permet de détecter la présence d'anomalies structurelles majeures dans près de 60 % des cas. (II-2A) 3. Lorsque la présence d'une anomalie structurelle foetale est soupçonnée ou identifiée, la patiente devrait être orientée vers les services d'une unité tertiaire d'échographie dès que possible en vue d'optimiser les options thérapeutiques. (II-2A) 4. Dans les cas de grossesse en cours présentant des anomalies structurelles foetales, l'examen échographique devrait être répété (à une fréquence établie en fonction de la ou des anomalies en question) afin d'évaluer l'évolution de la ou des anomalies et de tenter de détecter la présence d'autres anomalies n'ayant pas encore été identifiées, puisque cela pourrait influencer tant le counseling que la prise en charge obstétricale ou périnatale. (II-2B) 5. Lorsqu'une anomalie structurelle foetale est identifiée par échographie 2-D, le recours à d'autres techniques d'imagerie (telles que l'échocardiographie foetale, l'échographie obstétricale 3-D, l'IRM foetale ultra-rapide et, à l'occasion, la radiographie foetale et la tomodensitométrie foetale [au moyen d'un protocole à faible dose]) peut s'avérer utile dans certains cas particuliers. (II-2A) 6. Le recours à l'imagerie parentale devrait être envisagé dans certains cas particuliers, en fonction de l'anomalie foetale identifiée (p. ex. hérédité dominante potentielle). (III-A) 7. La tenue d'une analyse sanguine parentale et d'un dépistage prénatal effractif peut également s'avérer requise pour clarifier le diagnostic chez un foetus présentant des anomalies structurelles isolées ou multiples. (II-2A) 8. Les femmes devraient recevoir des renseignements au sujet de leurs résultats échographiques anormaux de façon claire, empathique et opportune, dans un milieu bienveillant qui assure le respect de la confidentialité. L'orientation vers les services de sous-spécialistes pédiatriques ou chirurgicaux appropriés devrait être envisagée afin de fournir les renseignements les plus précis possibles au sujet de la ou des anomalies et du pronostic connexe. (II-2 B) 9. Les parents devraient être avisés du fait qu'il est possible que les anomalies structurelles foetales majeures ou mineures, qu'elles soient isolées ou multiples, fassent partie d'un syndrome, d'une séquence ou d'une association génétique, malgré la présence d'un caryotype foetal normal. (III-A) 10. Dans les cas où une prise en charge postnatale précoce ou urgente pourrait s'avérer requise, l'accouchement dans un centre pouvant offrir les soins néonatals appropriés devrait être envisagé. (III-A) 11. Lorsqu'une quelconque anomalie structurelle congénitale a été identifiée pendant la période prénatale, la tenue d'une évaluation exhaustive du nouveau-né est essentielle aux fins du diagnostic et du counseling quant à l'étiologie, au pronostic et au risque de récurrence en ce qui concerne les futures grossesses, particulièrement dans les cas où l'étiologie n'a pas été clairement identifiée pendant la période prénatale. (III-A) 12. Dans les cas d'interruption de grossesse, de mortinaissance ou de décès néonatal, les professionnels de la santé devraient favoriser la tenue d'une autopsie complète par un pathologiste périnatal ou pédiatrique, et ce, afin d'obtenir un maximum de renseignements sur le diagnostic et l'étiologie de la ou des anomalies structurelles foetales. Lorsque la tenue d'une autopsie complète est refusée, les professionnels de la santé devraient favoriser la tenue d'une autopsie au moins partielle ou externe (y compris des radiographies et des photographies). (III-A) Validation : La présente opinion de comité a été rédigée par le comité sur la génétique et approuvée par le comité exécutif de la Société des obstétriciens et gynécologues du Canada.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 09/2009; 31(9):882-889.
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Alain Gagnon,
R Douglas Wilson,
Victoria M Allen,
François Audibert,
Claire Blight,
Jo-Ann Brock,
Valerie A Désilets,
Jo-Ann Johnson, Sylvie Langlois,
Lynn Murphy-Kaulbeck,
Philip Wyatt
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ABSTRACT: To provide information to genetic counsellors, midwives, nurses, and physicians who are involved in the prenatal care of women dealing with prenatally diagnosed isolated or multiple structural congenital anomalies.
To provide better counselling for women and families who are dealing with the diagnosis of a fetal structural anomaly.
Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library for relevant articles using appropriate controlled vocabulary (e.g., structural congenital anomalies, prenatal ultrasound diagnosis of congenital anomalies, invasive testing results, and diagnosis of genetic syndromes; soft markers of aneuploidy were not included in this search) and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and material from between 1985 and 2008 incorporated in the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The evidence obtained was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care.
Findings of isolated or multiple fetal anomalies on prenatal ultrasound examination always lead to stressful times for women and families. Although a proportion of such anomalies can be explained by chromosomal abnormalities (aneuploidy, unbalanced translocation, deletions, or duplications), others may represent recognizable syndromes with another genetic basis (microdeletion or autosomal dominant, recessive, or X-linked inheritance). Providing accurate information and relevant reproductive genetic counselling to these women and families will allow them to make informed decisions. This is not easily accomplished because of the limited information available prenatally. This document does not provide an extensive description of every syndrome but rather a framework of reference. No cost-benefit analysis is provided.
1. When a fetal structural anomaly is identified, the pregnant woman should be offered a timely consultation with a trained genetic counsellor and with a maternal-fetal medicine specialist and/or a medical geneticist. The counselling should be unbiased and respectful of the patient's choice, culture, religion, and beliefs. (III-A) 2. Patients should be informed that prenatal ultrasound at 18 to 20 weeks can detect major structural anomalies in approximately 60% of such cases. (II-2A) 3. When a fetal structural anomaly is suspected or identified, a referral to a tertiary ultrasound unit should be made as soon as possible to optimize therapeutic options. (II-2A) 4. In ongoing pregnancies with fetal structural anomalies, ultrasound examination should be repeated (at a frequency depending on the anomaly) to assess the evolution of the anomaly and attempt to detect other anomalies not previously identified, as this may influence the counselling as well as the obstetrical or perinatal management. (II-2B) 5. Once a fetal structural anomaly is identified by 2-D ultrasound, other imaging techniques such as fetal echocardiography, 3-D obstetrical ultrasound, ultrafast fetal MRI, and, occasionally, fetal X-ray and fetal CT scan (using a low-dose protocol) may be helpful in specific cases. (II-2A) 6. Parental imaging should be considered in specific cases, depending on the fetal anomaly identified (e.g., potential dominant inheritance). (III-A) 7. Parental blood testing and invasive prenatal testing may also be required to clarify the diagnosis for a fetus with isolated or multiple structural anomalies. (II-2A) 8. Women should receive information regarding the abnormal ultrasound findings in a clear, sympathetic, and timely fashion, and in a supportive environment that ensures privacy. Referral to the appropriate pediatric or surgical subspecialist(s) should be considered to provide the most accurate information possible concerning the anomaly or anomalies and the associated prognosis. (II-2 B) 9. Parents should be informed that major or minor fetal structural anomalies, whether isolated or multiple, may be part of a genetic syndrome, sequence, or association, despite a normal fetal karyotype. (III-A) 10. If early or urgent postnatal management may be required, delivery at a centre that can provide the appropriate neonatal care should be considered. (III-A) 11. When any congenital structural anomaly has been identified prenatally, a comprehensive newborn assessment is essential for diagnosis and counselling on the etiology, prognosis, and recurrence risk for future pregnancies, especially when the etiology has not been clearly identified prenatally. (III-A) 12. In cases of termination of pregnancy, stillbirth, or neonatal death, the health professional should encourage the performance of a complete autopsy by a perinatal or pediatric pathologist to provide maximum information on the diagnosis and etiology of the structural fetal anomaly or anomalies. When a complete autopsy is refused, the health professional should encourage the performance of at least a partial or external autopsy (including X-rays and photographs). (III-A) VALIDATION: This committee opinion has been prepared by the Genetics Committee of the SOGC and approved by the Executive of the SOGC.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 09/2009; 31(9):875-81, 882-9.
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ABSTRACT: To review the techniques and indications of preimplantation genetic testing, including preimplantation genetic diagnosis and screening.
Limited to an introductory discussion about the genetic aspects of preimplantation reproductive techniques.
This update does not discuss in detail the adverse outcomes that have been recorded in association with assisted reproductive technologies.
The Cochrane Library and Medline were searched for articles relating to preimplantation testing that were published from 1990 to February 2008, using the following terms: preimplantation genetic diagnosis, preimplantation genetic screening, and in vitro fertilization. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies.
This update is a consensus of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care.
This update educates readers about new genetic concepts, directions, and technology. The major harms and costs identified are those of assisted reproductive technologies.
The Society of Obstetricians and Gynaecologists of Canada.
Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders in couples at risk of transmitting a genetic condition to their offspring. Preimplantation genetic screening has been proposed to improve the effectiveness of in vitro fertilization in women of advanced maternal age or in couples with recurrent miscarriage or implantation failure, but the benefits of this approach are debated.
The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. 1. Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis. (III-A) 2. Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell. (II-2B) 3. Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result. (II-2B) 4. Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates. (III-A) 5. Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss. (I-D).
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 08/2009; 31(8):761-75.
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Sylvie Langlois,
Linlea Armstrong,
Kim Gall,
Gurdip Hulait,
Janet Livingston,
Tanya Nelson,
Patricia Power,
Denise Pugash,
Dawn Siciliano,
Michelle Steinraths,
André Mattman
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ABSTRACT: To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome.
We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy.
Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%).
The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus.
Prenatal Diagnosis 07/2009; 29(10):966-74. · 2.11 Impact Factor
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ABSTRACT: We report on a 14-year-old girl with mild cognitive impairment, deafness, and an unusual pattern of anomalies associated with a previously unreported de novo duplication of chromosome 17q21.33. The 1.1 Mb duplication was detected by Affymetrix 100K GeneChip array genome hybridization and involves the genomic region between 45,093,544 and 46,196,038 base pairs on chromosome 17 (NCBI build 36.1). The patient has microcephaly, unusual cup-shaped ears, scoliosis and other skeletal defects. Two genes involved in the duplicated region, PPP1R9B and COL1A1, are strong candidates for producing her phenotype.
American Journal of Medical Genetics Part A 06/2009; 149A(6):1257-62. · 2.39 Impact Factor
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ABSTRACT: We reviewed the available molecular cytogenetic techniques and their potential use in prenatal diagnosis of fetuses with multiple congenital anomalies and a "normal" standard chromosomal karyotype. We searched Medline to identify reports published after 1995 that were related to molecular prenatal diagnosis. After review, we reached the following conclusions: 1. In fetuses with a normal standard karyotype result, common chromosomal microdeletion syndromes may be suspected based on the pattern of congenital anomalies seen on prenatal ultrasound. 2. When a microdeletion syndrome is suspected based on the pattern of fetal anomalies, FISH testing for the specific molecular locus should be undertaken. 3. Routine chromosome analysis, which has been the gold standard for prenatal cytogenetic diagnosis, may in the future be replaced by microarray technology with increased diagnostic capability for smaller, submicroscopic genetic alterations associated with postnatal morbidity. 4. Microarray technology has been shown to increase our ability to make a diagnosis of known or new chromosomal deletion syndromes in pediatric populations with developmental delay. The use of this technology for prenatal diagnosis is currently limited but is likely to expand.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 06/2009; 31(5):414-21.
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ABSTRACT: To identify the decision-making factors and personal characteristics of women who opt for and against amniocentesis following a screen-positive maternal serum screen (MSS) result.
A questionnaire was mailed to 597 women who were randomly selected among women in the province of British Columbia (BC) who screened positive for Down syndrome (DS) on the MSS between January and June 2005. Subjects were evenly distributed across two main parameters: screen-positive women who opted for, and declined, amniocentesis (Groups 1 and 2, respectively).
Significant differences (P < 0.05) between Groups 1 and 2 include; reasons for wanting the MSS, post-positive MSS anxiety level, risk of miscarriage associated with amniocentesis, MSS risk estimate, reasons for wanting, or not wanting amniocentesis, normal fetal ultrasound, attitudes towards termination and religious beliefs. About half of all women across both groups did not find the MSS helpful in their pregnancy, primarily stating that it caused unnecessary increased anxiety.
To help avoid, or at least prepare women for the likelihood of increased anxiety following a screen-positive MSS result, and help prepare them for decision making, it is important to target MSS counselling to the individuality of the patient, and address these factors before MSS is undertaken.
Prenatal Diagnosis 03/2009; 29(5):514-9. · 2.11 Impact Factor
