Expanded carrier screening and preimplantation genetic diagnosis in a couple who delivered a baby affected with congenital factor VII deficiency

Abstract

BackgroundPreimplantation genetic diagnosis (PGD) is a powerful tool for preventing the transmission of Mendelian disorders from generation to generation. However, PGD only can identify monogenically inherited diseases, but not other potential monogenic pathologies. We aimed to use PGD to deliver a healthy baby without congenital FVII deficiency or other common Mendelian diseases in a couple in which both individuals carried a deleterious mutation in the F7 gene.MethodsAfter both members of the couple were confirmed to be carriers of the F7 gene mutation by Sanger sequencing, expanded carrier screening (ECS) for 623 recessive inheritance diseases was performed to detect pathological mutations in other genes. PGD and preimplantational genetic screening (PGS) were employed to exclude monogenic disorders and aneuploidy for their embryos.ResultsECS using targeted capture sequencing technology revealed that the couple carried the heterozygous disease-causative mutations c.3659C > T (p.Thr1220Ile) and c.3209G > A (p.Arg1070Gln) in the CFTR gene. After PGD and PGS, one of their embryos that was free of congenital FVII deficiency, cystic fibrosis (CF) and aneuploidy was transferred, resulting in the birth of a healthy 3200 g male infant.ConclusionWe successfully implemented PGD for congenital FVII deficiency and PGD after ECS to exclude CF for the first time to the best of our knowledge. Our work significantly improved the reproductive outcome for the couple and provides a clear example of the use of ECS combined with PGD to avoid the delivery of offspring affected not only by identified monogenically inherited diseases but also by other potential monogenic pathologies and aneuploidy.

RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders

“…The couples who underwent intracytoplasmic sperm injection-in vitro fertilisation (IVF) treatment to conceive children opted for preimplantation genetic testing (PGT). On day 5 after fertilisation, trophectoderm cells that had herniated out of the zona pellucida were selected for biopsy from blastocysts for subsequent genetic testing following previously described methods 19 20. Whole-genome amplification of trophectoderm cells was performed using a commercial kit (REPLI-gMidi Kit, QIAGEN, Germany) according to the manufacturer’s instructions.…”

Current attitudes and preconception towards expanded carrier screening in Eastern Chinese reproductive population

“…[11][12][13][14][15] However, the great majority of individuals in these studies are European or American, which have a relatively high socioeconomic status and high-quality medical services. Nowadays, ECS is already in an exploratory stage in China, [16][17][18] which highlights the feasibility and potential use of ECS. A growing number of Chinese reproductive individuals will be confronted with the choice to accept or refuse such a test.…”