Whole exome sequencing of aneuploid products of conception from consanguineous couples with recurrent pregnancy loss identified candidate genetic variants potentially associated with embryonic development and aneuploidy.
Recurrent pregnancy loss (RPL) affects approximately 1–2% of couples worldwide, and chromosomal abnormalities account for a substantial proportion of miscarriages. However, the contribution of rare fetal genetic variants to aneuploidy and early embryonic developmental competence remains poorly understood. First-trimester aneuploid products of conception (POCs) from five consanguineous couples with RPL were selected. Whole exome sequencing (WES) was performed with both targeted and non-targeted analyses to identify genes associated with miscarriage and aneuploidy. Candidate variants were classified by ACMG guidelines and confirmed by Sanger sequencing. Seventeen rare variants were found across 16 genes, including four novel candidate genes (SCLT1, HMCN1, ZNF780B, SHROOM1) involved in ciliogenesis, cytokinesis, transcription regulation, and cytoskeletal organization, and 13 novel variants in genes involved in mitotic regulation (MAD1L1, CCNB1, NCAPH), immune tolerance (PZP, CGAS, AXL, CD109, LRRFIP1), and implantation or vascular function (COL4A2, ANXA7, CFTR, SULT1A1). Segregation analysis suggested a potential role for homozygous and trans compound heterozygous variants in SCLT1 and NCAPH, respectively. These findings identify rare variants in 16 genes, including four novel candidates, as biologically plausible candidate genes potentially associated with early embryonic developmental competence and aneuploidy risk in embryos or parental gametes. Findings with limited supporting evidence should be interpreted as hypothesis-generating and may serve as a basis for future functional validation studies and genetic counseling considerations.
Recurrent pregnancy loss (RPL) affects approximately 1–2% of couples worldwide, and chromosomal abnormalities account for a substantial proportion of miscarriages. However, the contribution of rare fetal genetic variants to aneuploidy and early embryonic developmental competence remains poorly understood. First-trimester aneuploid products of conception (POCs) from five consanguineous couples with RPL were selected. Whole exome sequencing (WES) was performed with both targeted and non-targeted analyses to identify genes associated with miscarriage and aneuploidy. Candidate variants were classified by ACMG guidelines and confirmed by Sanger sequencing. Seventeen rare variants were found across 16 genes, including four novel candidate genes (SCLT1, HMCN1, ZNF780B, SHROOM1) involved in ciliogenesis, cytokinesis, transcription regulation, and cytoskeletal organization, and 13 novel variants in genes involved in mitotic regulation (MAD1L1, CCNB1, NCAPH), immune tolerance (PZP, CGAS, AXL, CD109, LRRFIP1), and implantation or vascular function (COL4A2, ANXA7, CFTR, SULT1A1). Segregation analysis suggested a potential role for homozygous and trans compound heterozygous variants in SCLT1 and NCAPH, respectively. These findings identify rare variants in 16 genes, including four novel candidates, as biologically plausible candidate genes potentially associated with early embryonic developmental competence and aneuploidy risk in embryos or parental gametes. Findings with limited supporting evidence should be interpreted as hypothesis-generating and may serve as a basis for future functional validation studies and genetic counseling considerations.
Royan Institute for Reproductive Biomedicine, ACECR