Lenaick Gourhant1, Ozvan Bocher2, Luc De Saint Martin1, Thomas E Ludwig2, Anne Boland3, Jean F Deleuze3, Philippe Merviel4, Pierre F Dupré5, Catherine A Lemarié6, Francis Couturaud7, Cédric Le Maréchal8, Emmanuelle Génin2, Elisabeth Pasquier9. 1. Université de Brest, EA 3878 (GETBO) Brest 29609, France. 2. Université de Brest, Inserm, EFS, UMR 1078, GGB, CHU de Brest, Brest 29200, France. 3. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry 91057, France. 4. Université de Brest, EA 3878 (GETBO) Brest 29609, France; Division of Gynaecology, University Hospital of Brest Brest 29609, France. 5. Université de Brest, Inserm, EFS, UMR 1078, GGB, CHU de Brest, Brest 29200, France; Division of Gynaecology, University Hospital of Brest Brest 29609, France. 6. Université de Brest, EA 3878 (GETBO) Brest 29609, France; Université de Brest, Inserm, EFS, UMR 1078, GGB, CHU de Brest, Brest 29200, France. 7. Université de Brest, EA 3878 (GETBO) Brest 29609, France; Université de Brest, Centre d'Investigation Clinique, INSERM CIC 1412 Brest 29609, France. 8. Université de Brest, Inserm, EFS, UMR 1078, GGB, CHU de Brest, Brest 29200, France; Université de Brest, Laboratoire de Génétique Moléculaire et d'Histocompatibilité Brest 29609, France. 9. Université de Brest, EA 3878 (GETBO) Brest 29609, France. Electronic address: elisabeth.pasquier@chu-brest.fr.
Abstract
RESEARCH QUESTION: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)? DESIGN: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES). RESULTS: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052). CONCLUSIONS: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.
RESEARCH QUESTION: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)? DESIGN: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES). RESULTS: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052). CONCLUSIONS: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.
Authors: Kathryn W Juchem; Anshu P Gounder; Jian Ping Gao; Elise Seccareccia; Narayana Yeddula; Nicholas J Huffmaster; Alexandra Côté-Martin; Steven E Fogal; Donald Souza; Sarah Sirui Wang; Elizabeth R A Glynn; Ivy Yung; Julie Ritchie; Li Li; Jie Zheng; M Lamine Mbow; Jun Li; Sumit K Chanda Journal: Front Immunol Date: 2022-01-13 Impact factor: 7.561