The investigation of cell free DNA and genetic causes in the evaluation of miscarriage

Colley, Emily Charlotte (2021). The investigation of cell free DNA and genetic causes in the evaluation of miscarriage. University of Birmingham. Ph.D.

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Approximately one in four pregnancies result in pregnancy loss, with 1 % of couples suffering from recurrent miscarriage. Genetic investigations are recommended after three consecutive miscarriages and require pregnancy tissue. This thesis investigates the use of cell-free fetal DNA from maternal blood to identify chromosomal abnormalities in recurrent miscarriage. 123 cell-free DNA samples were collected from first trimester miscarriages (5+1 to 11+6 weeks) and 62 % of samples had a corresponding routine cytogenetic result. 54 % of genetic aberrations were correctly identified using single end sequencing on a HiSeq2500 and the WISECONDOR pipeline, and 68 % of genetic aberrations were correctly identified using paired end sequencing on a NextSeq and the Illumina pipeline. This thesis also investigates other genetic causes of miscarriage in euploid pregnancies and includes a published systematic review and whole exome sequencing in seven euploid miscarriage trios. The systematic review identified 50 studies which included variants thought to be causative of miscarriage, and the whole exome sequencing cohort demonstrated the difficulty in interpreting variants without human phenotype ontology or genes without a reported disease-association. However, identification of genes/ variants that are causative of or predisposing to miscarriage will be of significant individual patient impact with respect to counselling and treatment.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Metabolism and Systems Research
Funders: Other
Other Funders: Tommy's Baby Charity
Subjects: R Medicine > RG Gynecology and obstetrics


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