Conclusion
We have successfully implemented a noninvasive method to predict fetal GCK genotype using cell-free DNA in 3 pregnant women carrying an inactivating GCK variant. This method could guide tailoring of hyperglycemia treatment in pregnancies of women with GCK monogenic diabetes.
Methods
This was a proof-of-concept study involving 3 pregnant women with a causal GCK variant that used information from 1) massive parallel sequencing of maternal plasma cell-free DNA, 2) direct haplotype sequences of maternal genomic DNA, and 3) the paternal genotypes to estimate relative haplotype dosage of the pathogenic variant-linked haplotype. Statistical testing of variant inheritance was performed using a sequential probability ratio test (SPRT).
Objective
This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA.
Results
In each of the 3 cases, plasma cell-free DNA was extracted once between gestational weeks 24 and 36. The fetal fraction of cell-free DNA ranged from 21.8% to 23.0%. Paternal homozygous alleles that were identical to the maternal GCK variant-linked allele were not overrepresented in the cell-free DNA. Paternal homozygous alleles that were identical to the maternal wild-type-linked allele were significantly overrepresented. Based on the SPRT, we predicted that all 3 cases did not inherit the GCK variant. Postnatal infant genotyping confirmed our prediction in each case.