Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage

REPRODUCTIVE BIOMEDICINE ONLINE

卷:42

Article

Gourhant, Lenaick¹  Bocher, Ozvan²  De Saint Martin, Luc¹  Ludwig, Thomas E.²  Boland, Anne³  Deleuze, Jean F.³  Merviel, Philippe^1,4  Dupre, Pierre F.^2,4  Lemarie, Catherine A.^1,2  Couturaud, Francis^1,5  Le Marechal, Cedric^2,6  Genin, Emmanuelle²  Pasquier, Elisabeth¹ 

[1] Univ Brest, EA GETBO 3878, F-29609 Brest, France

[2] Univ Brest, CHU Brest, EFS, INSERM,UMR 1078,GGB, F-29200 Brest, France

[3] Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, F-91057 Evry, France

[4] Univ Hosp Brest, Div Gynaecol, F-29609 Brest, France

[5] Univ Brest, Ctr Invest Clin, INSERM, CIC 1412, F-29609 Brest, France

[6] Univ Brest, Lab Genet Mol & Histocompatibilite, F-29609 Brest, France

关键词: Extreme phenotype;    Holotranscobalamin;    Rare variants;    Recurrent early miscarriage;    TCN2 gene;    Whole exome sequencing;   

DOI  :  10.1016/j.rbmo.2021.01.008

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free