scholarly journals PREIMPLANTATION GENETIC TESTING: Preimplantation genetic testing for polygenic disease risk

Reproduction ◽  
2020 ◽  
Vol 160 (5) ◽  
pp. A13-A17 ◽  
Author(s):  
Nathan R Treff ◽  
Diego Marin ◽  
Louis Lello ◽  
Stephen Hsu ◽  
Laurent C A M Tellier
Keyword(s):  
Clinical Practice ◽  
Genetic Testing ◽  
Disease Risk ◽  
Population Level ◽  
Standard Of Care ◽  
Primary Objective ◽  
Monogenic Disease ◽  
Preimplantation Genetic Testing ◽  
Polygenic Disease ◽  
Risk Scoring

Since its introduction to clinical practice, preimplantation genetic testing (PGT) has become a standard of care for couples at risk of having children with monogenic disease and for chromosomal aneuploidy to improve outcomes for patients with infertility. The primary objective of PGT is to reduce the risk of miscarriage and genetic disease and to improve the success of infertility treatment with the delivery of a healthy child. Until recently, the application of PGT to more common but complex polygenic disease was not possible, as the genetic contribution to polygenic disease has been difficult to determine, and the concept of embryo selection across multiple genetic loci has been difficult to comprehend. Several achievements, including the ability to obtain accurate, genome-wide genotypes of the human embryo and the development of population-level biobanks, have now made PGT for polygenic disease risk applicable in clinical practice. With the rapid advances in embryonic polygenic risk scoring, diverse considerations beyond technical capability have been introduced.

scholarly journals Haplotyping by linked-read sequencing (HLRS) of the genetic disease carriers for preimplantation genetic testing without a proband or relatives

2020 ◽  
Author(s):  
Qing Li ◽  
Yan Mao ◽  
Shaoying Li ◽  
Hongzi Du ◽  
Wenzhi He ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Disease ◽  
De Novo ◽  
Monogenic Disease ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Preimplantation Genetic Testing ◽  
Linkage Analyses ◽  
Alpha Thalassemia ◽  
Polar Bodies

Abstract Background: In order to mitigate the risk of allele dropout (ADO) and ensure the accuracy of preimplantation genetic testing for monogenic disease (PGT-M), it is necessary to construct parental haplotypes.. Typically, haplotype resolution is obtained by genotyping multiple polymorphic markers in both parents and a proband or a relative. Sometimes, single sperm typing, or tests on the polar bodies may also be useful. Nevertheless, this process is time-consuming. At present, there was no simple linkage analysis strategy for patients without affected relatives.Method: To solve this problem, we established a haplotyping by linked-read sequencing (HLRS) method without the requirement for additional relatives. First, the haplotype of the genetic disease carriers in the family was constructed by linked-read sequencing, and then the informative single nucleotide polymorphisms (SNPs) in upstream and downstream mutation region were selected to construct the embryo haplotype and to determine whether the embryo was carrying the mutation. Two families were selected to validate this method; one with alpha thalassemia and the other with NDP gene disorder.Results: The haplotyping by linked-read sequencing (HLRS) method was successfully applied to construct parental haplotypes without recruiting additional family members; the method was also validated for PGT-M. The mutation carriers in these families were sequenced by linked-read sequencing, and their haplotypes were successfully phased. Adjacent SNPs of the mutation gene were identified. The informative SNPs were chosen for linkage analyses to identify the carrier embryos. For the alpha thalassemia family, a normal blastocyst was transferred to the uterus and the accuracy of PGT-M was confirmed by amniocentesis at 16 weeks of gestation. Conclusions: Our results suggest that HLRS can be applied for PGT-M of monogenic disorders or de novo mutations where the mutations haplotype cannot be determined due to absence of affected relatives. Keywords: Preimplantation Genetic Testing for monogenic disease, Linked-read sequencing, Linkage analyses, Haplotype

scholarly journals Preimplantation Genetic Testing for Polygenic Disease Relative Risk Reduction: Evaluation of Genomic Index Performance in 11,883 Adult Sibling Pairs

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 648 ◽  
Author(s):  
Nathan R. Treff ◽  
Jennifer Eccles ◽  
Diego Marin ◽  
Edward Messick ◽  
Louis Lello ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Relative Risk ◽  
Risk Reduction ◽  
Relative Risk Reduction ◽  
Embryo Selection ◽  
Type I ◽  
Preimplantation Genetic Testing ◽  
Sibling Pairs ◽  
Polygenic Disease ◽  
Diabetes Status

Preimplantation genetic testing for polygenic disease risk (PGT-P) represents a new tool to aid in embryo selection. Previous studies demonstrated the ability to obtain necessary genotypes in the embryo with accuracy equivalent to in adults. When applied to select adult siblings with known type I diabetes status, a reduction in disease incidence of 45–72% compared to random selection was achieved. This study extends analysis to 11,883 sibling pairs to evaluate clinical utility of embryo selection with PGT-P. Results demonstrate simultaneous relative risk reduction of all diseases tested in parallel, which included diabetes, cancer, and heart disease, and indicate applicability beyond patients with a known family history of disease.

68. PREIMPLANTATION GENETIC TESTING OF MONOGENIC DISEASE: EXPERIENCE IN RUSSIA

2019 ◽  
Vol 39 ◽  
pp. e68-e69
Author(s):  
S. Zhikrivetskaya Olegovna ◽  
Y. Volkova Leonidovna ◽  
E. Musatova Valerievna ◽  
Y. Sofronova Vladislavovna ◽  
N. Shirokova Anatolievna ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Monogenic Disease ◽  
Preimplantation Genetic Testing ◽  
Disease Experience

Facilitated cascade testing (FaCT): a randomized controlled trial

2020 ◽  
pp. ijgc-2020-002118
Author(s):  
Roni Nitecki ◽  
Haley A Moss ◽  
Catherine H Watson ◽  
Diana L Urbauer ◽  
Alexander Melamed ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Controlled Trial ◽  
Randomized Study ◽  
Standard Of Care ◽  
Pathogenic Mutation ◽  
Primary Objective ◽  
Care Group ◽  
Patient Navigator ◽  
Cascade Testing ◽  
First Degree Relatives

BackgroundIdentifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing.Primary objectiveOur primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing.Study hypothesisWe hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care.Trial designThe FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services.Major inclusion/exclusion criteriaAdult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included.Primary endpointAnalyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm.Sample sizeOne hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants.Estimated dates for completing accrual and presenting resultsJanuary 2024.Trial registrationNCT04613440

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