Patients with inactivating glucokinase (GCK) mutation usually do not require treatment except for during pregnancy. The decision to treat hyperglycemia during pregnancy would depend on the fetal GCK genotype. However, it has not been able to noninvasively investigate the fetal genotype antenatally. In this study, we developed a method to determine cell-free fetal genotype of GCK and applied it in a case of pregnant woman with GCK mutation. A 40 years old woman in her second pregnancy presented with hyperglycemia. She was diagnosed with GCK p.Gly411Ser (chr7:44185121C>T; NM_000162 c.G1228A) mutation prior to her second pregnancy. We used targeted linked-read deep sequencing to resolve the haplotypes of GCK for both the women and her husband. Cell-free DNA was extracted from maternal plasma at week 24 of gestation and were subjected to massively parallel sequencing. The allelic fraction of the heterozygous variants that were in maternal mutant-linked haplotype were analyzed. The fetal fraction of the maternal plasma cell-free DNA was 21.8%. In maternal plasma cell-free DNA, a total of 12 heterozygous variants, that were homozygous in paternal genomic DNA, were identified within 40 kb of the disease-causing mutation. The average allelic fraction of the 12 variants in the mutant-linked haplotype and the wild type-linked haplotype in the cell-free DNA was 44.1% and 55.9%, respectively. This significant difference in allelic fraction of the haplotypes suggested that the fetus did not inherit the GCK mutant-linked haplotype (P 0.0081). The inferred fetal genotype was available at week 30 of gestation and the patient was treated with basal-bolus insulin therapy until term at 38 weeks. The fetal birth weight was 2,980 g (25th percentile). The fetal genotype of GCK was confirmed by Sanger sequencing postnatally. This was the first study to use cell-free DNA to determine fetal genotype to guide treatment of hyperglycemia in pregnant women with GCK mutation.


S. Kwak: None. S. Jang: None. S. Kang: None. H. Jang: None. S. Lee: None. J. Chae: None. K. Park: None.


Korean Ministry of Health and Welfare (HI15C3131, HI13C1468)

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