Technical aspects of reproductive genetics (Methods of PGS, PGD, Prenatal)


Speaker:

Darren Griffin,UK

 

 

Speaker BIO:

griffin darren 2013- Fellow of the Royal Society for the encouragement of Arts, Manufactures and Commerce (FRSA)
2011- President - International Chromosome and Genome Society (VP from 2008)
2008- Doctor of Science (DSc), University of Manchester
2007- Fellow of the Royal College of Pathologists (FRCPath)
2002- Postgraduate Certificate in Teaching and Learning in Higher Education, Brunel University (PGCertHE)
2001- Editorial Board “Prenatal Diagnosis”
2000- Fellow of the Society of Biology (CBiol, FSB)
1992- Doctor of Philosophy (PhD), Human Genetics, University College London
1988- Bachelor of Science (BSc), Genetics and Cell Biology, University of Manchester

 

 

Overview

Counting chromosomes is, in effect, the original PGD in that Bob Edwards detected the Barr body (inactive sex chromosome in females) to sex rabbit preimplantation embryos in 1968. When applied clinically in the early 1990s, following the realization that the oft-lauded Y chromosomePCR based sexing approach would inevitably prove unreliable, attention turned to FISH as a means of selecting female only embryos in families at risk of transmitting sex linked disorders. A highly successful method of FISH sexing using X and Y probes lasted for nearly 20 years. An obvious next step was to target carriers translocation carriers and the subsequent FISH-based approach was only superseded when array-based approaches became commonplace. FISH also persisted from the late 1990s to the mid 2000s and the screening for aneuploidy became the most widespread means of performing PGD. Following the results of randomised trials “PGS” became a buzzword for all that is bad about PGD and, with it, the much-used multicolour FISH (mFISH) based approach fell into disrepute. Array CGH ultimately came to the rescue and the newly badged “PGD-A” now analyses products of polar body or trophectoderm biopsy to great effect. Array CGH is also helping us to understand the fundamentals of early human development and why cleavage stage PGS was such a disaster. An emerging picture of a “fluid” karyotype from cell to cell in early cleavage divisions is emerging, stabilising by blastulation. High-density SNP genotyping takes chromosome counting a step further by detecting phase and parent of origin of the error. Karyomapping uses the outputs of SNP array interrogation, traces parental haplotypes and identifies the independent segregation patterns of parental chromosomes as well as patterns of recombination. This allows simultaneous detection of aneuploidy, uniparental disomy, unbalanced structural rearrangements and, by linkage, the presence of any inherited disease-related monogenic trait. Clinical validation of Karyomapping has been successful and has recently resulted in unaffected live births. The principles of Karyomapping also contain inherent future proofing in that the algorithm is as applicable to next generation sequencing data.