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Preimplantation Genetic Diagnosis (PGD) for Gertmann-Sträussler-Scheinker Syndrome (GSS) Determined by an Autosomal Dominant Mutation in the Prion Protein Gene (PRNP)
A, Pedigree showing that the maternal partner is a 27-year-old asymptomatic woman with an F198S mutation identified by predictive testing in a family with a known history of GSS due to an F198S mutation in the PRNP gene (phenylalanine to serine substitution at codon 198). Marker order in relation to the gene is shown on the left. B, Sequential PB1 and PB2 mutation analysis in 12 oocytes, with the results available for 9 oocytes, 4 of which had the mutation, including 1 recombinant oocyte (oocyte 13). The remaining 5 oocytes with DNA results were free of the F198S mutation (oocytes 2, 3, 7, 10, and 14), 3 of which were from oocytes with heterozygous PB1 and hemizygous mutant PB2 (oocytes 7, 10, and 14). C. Blastomere analysis of 8 embryos deriving either from the oocytes with failed amplification of PB1, ADO of linked markers, or from affected oocytes for confirmation. This analysis allowed detecting 1 additional mutation-free embryo for transfer (embryo 1), deriving from a mutation-free oocyte and confirmed normal. Two healthy embryos were transferred, resulting in the birth of healthy twins with a very high likelihood (91%-98%) of being free of the F198S mutation, likely without predisposition to this familial fatal prion-related neurodegenerative disorder. ADO, allele dropout, refers to the inability to detect an allele during polymerase chain reaction (PCR) through amplification of linked markers; FA, failed amplification, the inability to amplify the gene of interest via PCR; PB1, the first polar body, extruded from the mature oocyte and the outcome of meiosis I, containing 2 copies of maternal DNA; PB2, the second polar body, extruded following fertilization of the oocyte and the outcome of meiosis II, containing 1 copy of maternal DNA.