Offering preimplantation genetic testing for monogenic disorders (PGT‐M) for conditions with reduced penetrance or variants of uncertain significance: Ethical insight from U.S. laboratory genetic counselors

2021 ◽  
Author(s):  
Anthony Porto ◽  
Rikki Gaber Caffrey ◽  
Megan Crowley‐Matoka ◽  
Sara Spencer ◽  
Mindy Li ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Counselors ◽  
Preimplantation Genetic Testing ◽  
Variants Of Uncertain Significance ◽  
Monogenic Disorders ◽  
Uncertain Significance ◽  
Reduced Penetrance

scholarly journals Preimplantation Genetic Testing for Monogenic Disorders

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 871 ◽  
Author(s):  
Martine De Rycke ◽  
Veerle Berckmoes
Keyword(s):  
Genetic Testing ◽  
Whole Genome Amplification ◽  
State Of The Art ◽  
Snp Array ◽  
Genetic Data ◽  
Monogenic Disorder ◽  
Preimplantation Genetic Testing ◽  
Monogenic Disorders ◽  
The Cost ◽  
Concurrent Analysis

Preimplantation genetic testing (PGT) has evolved into a well-established alternative to invasive prenatal diagnosis, even though genetic testing of single or few cells is quite challenging. PGT-M is in theory available for any monogenic disorder for which the disease-causing locus has been unequivocally identified. In practice, the list of indications for which PGT is allowed may vary substantially from country to country, depending on PGT regulation. Technically, the switch from multiplex PCR to robust generic workflows with whole genome amplification followed by SNP array or NGS represents a major improvement of the last decade: the waiting time for the couples has been substantially reduced since the customized preclinical workup can be omitted and the workload for the laboratories has decreased. Another evolution is that the generic methods now allow for concurrent analysis of PGT-M and PGT-A. As innovative algorithms are being developed and the cost of sequencing continues to decline, the field of PGT moves forward to a sequencing-based, all-in-one solution for PGT-M, PGT-SR, and PGT-A. This will generate a vast amount of complex genetic data entailing new challenges for genetic counseling. In this review, we summarize the state-of-the-art for PGT-M and reflect on its future.

Variants of uncertain significance in BRCA testing: Impact on risk perception, worry, prevention, and counseling.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1555-1555
Author(s):  
Tracy Graham ◽  
Andrea Eisen ◽  
Sue Richter ◽  
Iman Haroun ◽  
Ellen Warner
Keyword(s):  
Risk Perception ◽  
Perceived Risk ◽  
Clinical Decision Making ◽  
Economic Status ◽  
Genetic Counselors ◽  
Prophylactic Surgery ◽  
Provider Attitudes ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Referring Physicians

1555 Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool in clinical decision-making. Variants of uncertain significance (VUS) can occur in up to 25% of individuals and pose clinical challenges. We compared i) result recall ii) risk perception iii) worry and iv) risk modifying behaviours in individuals with VUS, a pathogenic mutation (PM) or an uninformative result (UR). Care provider attitudes to VUS were also studied. Methods: A questionnaire was mailed to women testing positive for a VUS, PM or UR. Items included demographics, time from disclosure, result recall and cancer worry using the validated Trask score. Likelihood of risk modifying behaviours or intensified screening was evaluated by 5 point Likert scale. 9 regional genetic counselors and 11 referring physicians were surveyed on VUS management. Responses were evaluated by chi square and ANOVA. Results: All groups had similar age, marital status and education. Failure to correctly identify a result as uninformative occurred in 32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) had personal history of breast cancer. Perceived risk increased after disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p<0.001). Mean Trask scores were 7.6 (VUS) and 9.8 (PMC) (p=0.006, t-test). In affected patients, mastectomy was 22% (VUS) and 55% (PMC) (p=0.01), oophorectomy 39% (VUS) and 85% (PMCs) (p<0.001) with75% and 95% intensified screening 75% in unaffected VUS and PM (p=0.16). 3% (VUS) and 6% (PMC) agreed with chemoprophylaxis (p=NS). Genetic counselors unanimously reported low comprehension in VUS vs PM. VUS was disclosed only 75% of the time with poor comprehension, perceived anxiety and negative family history as reasons. Referring physicians recommended predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 1/3 of patients fail to recall their VUS as uninformative. Perceived risk was increased after VUS disclosure but lower than PMC. Worry scores showed impact on daily functioning. Uptake of prophylactic surgery was lower in affected VUS vs PMC carriers with similar rates of intensified screening if unaffected. Patients with low economic status or anxiety are at particular risk of incomplete counseling.

scholarly journals Thermodynamic destabilization informs pathogenicity assessment of a variant of uncertain significance in cardiac myosin binding protein C

2019 ◽  
Author(s):  
Maria Rosaria Pricolo ◽  
Elías Herrero-Galán ◽  
Cristina Mazzaccara ◽  
Maria Angela Losi ◽  
Jorge Alegre-Cebollada ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Rna Splicing ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Variants Of Uncertain Significance ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Uncertain Significance ◽  
Myosin Binding

ABSTRACTIn the era of Next Generation Sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for Hypertrophic Cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3.

scholarly journals Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study

Circulation ◽  
2021 ◽  
Author(s):  
Andrew M Glazer ◽  
Giovanni E. Davogustto ◽  
Christian M. Shaffer ◽  
Carlos G Vanoye ◽  
Reshma R. Desai ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Disease Risk ◽  
Large Population ◽  
Hek293 Cells ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Functional Evaluation ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability. Methods: The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.

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