Fig. 4: Clinical utility of Haploseek for preimplantation genetic testing for monogenic disease (PGT-M) of X-linked disorders.

(a) A pedigree of family 15, in which the mother and maternal grandmother (of embryo 101Q-2) are both heterozygous for a premutation allele at the FMR1 gene locus on chrX. For haplotype phasing of the mother, the maternal grandmother’s DNA was genotyped. (b) Screen captures of Haploseek haplotype prediction plots for the familial FMR1 premutation allele in embryo biopsy 101Q-2 of family 15. The approximate location of the FMR1 gene is marked by a dashed vertical line. Results are depicted as in Fig. 3c, except that the haplotype predictions are for the +/−2 Mb flanking region of the FMR1 gene on chrX. The pictured sample exhibits a high-confidence maternal grandfather haplotype at the family premutation site. Since the maternal grandfather does not carry the FMR1 premutation, the embryo is wild type. This result and all other clinical applications of Haploseek for X-linked diseases (summarized in Table S4) were validated by polymerase chain reaction (PCR)-based PGT-M. Note that Haploseek does not output paternal haplotype predictions on chrX because male embryos do not have a paternal chrX and female embryos have a known non-PAR paternal chrX haplotype. Hence, the marginal probability is marked on the plot as 0.5 for the entire paternal haplotype and the paternal haplotype prediction should be ignored.