Soo Heon Kwak1,2, Camille E Powe2,3,4, Se Song Jang5, Michael J Callahan3, Sarah N Bernstein4,6, Seung Mi Lee7, Sunyoung Kang1,8, Kyong Soo Park1,8,9, Hak C Jang8,10, Jose C Florez2,3,4,11, Jong-Il Kim12,13, Jong Hee Chae5,14. 1. Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea. 2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 3. Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA 02114-2696, USA. 4. Harvard Medical School, Boston, MA 02115, USA. 5. Department of Pediatrics, Seoul National University Children's Hospital, Seoul 03080, Korea. 6. Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Massachusetts General Hospital, Boston, MA 02114-2696, USA. 7. Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Korea. 8. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea. 9. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea. 10. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea. 11. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114-2696, USA. 12. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea. 13. Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea. 14. Department of Genomic Medicine, Seoul National University Hospital, Seoul 03080, Korea.
Abstract
CONTEXT: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. OBJECTIVE: This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. 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). 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. 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.
CONTEXT: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. OBJECTIVE: This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. 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). 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. 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.
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