Publications by authors named "D James Stavropoulos"

98 Publications

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists.

J Med Genet 2021 Sep 20. Epub 2021 Sep 20.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Purpose And Scope: The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems.

Methods Of Statement Development: A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021.

Results And Conclusions: The use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.
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http://dx.doi.org/10.1136/jmedgenet-2021-107897DOI Listing
September 2021

Defining and Reporting on Critical Values in Genetics: A Laboratory Survey.

J Appl Lab Med 2021 Sep;6(5):1299-1304

Quality Council, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Background: Although an obvious critical value in metabolic genetics would be ammonia, it is more challenging to define critical values in molecular genetics and cytogenetics. The objective of this study was to survey genetic laboratories in Ontario, Canada, to determine whether different centers considered similar results as critical and thus potentially deserving of a different reporting process.

Methods: An online 11-question survey was emailed to Ontario laboratory directors, and the results were analyzed.

Results: The response rate was 82% (9/11). Cytogenetics and molecular genetics services were each provided by 7 of the 9 centers, with 3 centers providing biochemical/metabolic genetics services and 1 providing maternal marker serum screening services. The case type (e.g., prenatal, newborn, or expedited by the ordering physician) was one factor. Quantitative fluorescence PCR for autosomal aneuploidy, pathogenic variants in both prenatal and postnatal settings, and oncological results were considered critical cytogenetics results. Pathogenic prenatal cases, indeterminate results, and unexpected results were considered more critical for molecular genetics. Critical results were more likely to prompt a telephone call or email to the ordering physician.

Conclusion: Ontario genetics laboratories tended to have similar reporting processes for critical results. Both the types of cases and the pathogenicity of the result define what values are considered critical.
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http://dx.doi.org/10.1093/jalm/jfab040DOI Listing
September 2021

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mol Psychiatry 2021 05 17;26(5):1706-1718. Epub 2021 Feb 17.

The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
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http://dx.doi.org/10.1038/s41380-021-01035-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159744PMC
May 2021

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh.

NPJ Genom Med 2021 Feb 16;6(1):14. Epub 2021 Feb 16.

College of Medicine, Mohammed Bin Rashid University of Medicine and Health Science, Dubai, UAE.

Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.
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http://dx.doi.org/10.1038/s41525-021-00173-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887195PMC
February 2021

Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease.

NPJ Genom Med 2020 23;5:47. Epub 2020 Oct 23.

Broad Institute of MIT and Harvard, Cambridge, MA USA.

Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders; however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading healthcare and research organizations in the US and Canada, was formed to expand access to high-quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders, and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice, and support safe and effective WGS testing for diagnosis of germline disease.
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http://dx.doi.org/10.1038/s41525-020-00154-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585436PMC
October 2020
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