Abstract
The first application of preimplantation genetic diagnosis (PGD) recently celebrated its 25th birthday. Aside from the very early days when chromosomal diagnoses were used (by sexing) for the selective implantation of embryos unaffected by sex linked disorders, the paths of chromosomal and monogenic PGD have diverged. For monogenic disorders, progress has been impeded by the need to tailor each diagnosis to the mutation in question. For chromosomal diagnoses, fluorescent in situ hybridization (FISH) technology was replaced by array comparative genomic hybridization (aCGH), and then next generation sequencing (NGS). Karyomapping is a novel approach that allows the detection of the inheritance of (grand) parental haploblocks through the identification of inherited chromosomal segments. It involves genome-wide single nucleotide polymorphism (SNP) analysis of parental DNA, a reference from a related individual of known disease status (typically an affected child) and amplified DNA form biopsied cells of the (usually blastocyst) embryos in question. Identification of informative loci for each of four parental haplotypes is followed by direct comparison to the reference, ultimately creating a Karyomap. The Karyomapping programme (Illumina) displays homologous chromosomes, points of crossing over and the haplotype of each of the embryos. It also detects meiotic trisomy, monosomy, triploidy and uniparental heterodisomy (some of which NGS and aCGH will not). Inherent in the design is the analysis of “key SNPs” (heterozygous informative calls) thereby avoiding the risk of misdiagnoses caused by the phenomenon of allele drop out (ADO). Karyomapping is currently in use for the detection of monogenic disorders and around 1000 clinics offer it worldwide making use of about 20 diagnostic laboratories. At the time of writing, over two and a half thousand clinical cases have been performed. Because of the limited detection of some post-zygotic errors such as post-zygotic trisomy which can also lead to mosaicism, Karyomapping has not yet been fully applied clinically for aneuploidy screening. The diagnostic potential of the technique will be fully recognised with the application of this technology on clinical cases.