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Sequence Diversity Declines Early in Pregnancy
- Researchers found a notable enrichment of pathogenic single nucleotide variants (SSVs) and loss-of-function mutations in cases of pregnancy loss, shedding light on genetic factors contributing to fetal demise.
- De novo mutations and inherited variants previously unassociated with developmental disorders appeared to play a significant role in miscarriage, with pathogenic variants spread across fetal samples.
- Most pathogenic variants detected were de novo, suggesting spontaneous origin in the embryo or parental germ cells, while a subset indicated biallelic inheritance with a higher recurrence risk in subsequent pregnancies.
- Even when direct fetal samples were lacking, pathogenicity assessments based on allele balance between fetal and villus-derived DNMs remained consistent, with a strong paternal bias in the origin of these mutations.
- Compared to controls, there was a threefold enrichment of deleterious SSVs in pregnancy loss cases, emphasizing the biological relevance of these mutations in early embryonic lethality.
- Delving into chromosomal ploidy status, the study highlighted a more pronounced enrichment of pathogenic mutations in euploid fetuses, indicating distinct pathways to pregnancy loss besides gross chromosomal abnormalities.
- Analyses of highly constrained genes revealed a fourfold increased rate of loss-of-function mutations in euploid pregnancy losses compared to controls, suggesting additional genetic risk factors impacting embryonic development.
- Identification of novel candidate genes like DDX5, ZMYM4, and HECTD1 implicated in pregnancy loss opens new avenues for understanding genetic contributors to embryonic viability beyond known disease genes.
- Functional annotation of mutated genes according to fetal tissue expression patterns and phenotypic associations underscored the influence of disruptions to highly active developmental genes on pregnancy outcomes during early gestation.
- The research identified a homozygous loss-of-function variant in DHCR7 and compound heterozygous mutations in CPLANE1, emphasizing the impact of biallelic genotypes on early gestational failure and recurrence risks in affected families.
- Differentiating between de novo and biallelic inherited mutations is crucial for clinical risk assessment, with de novo variants posing isolated risks while biallelic variants potentially leading to persistent recurrence risks in subsequent pregnancies.
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