Sequence Diversity Lost in Early Pregnancy

Area of Science:

• Genetics
• Reproductive Biology
• Genomic Medicine

Background:

• Germline mutations are heritable and occur before fertilization.
• De novo mutations (DNMs) are well-studied, with most originating paternally.
• Early pregnancy loss is understudied, with few known causes or interventions.

Purpose of the Study:

• To understand the sequence diversity and genetic causes of early pregnancy loss.
• To investigate the interplay between meiotic recombination and point mutations in pregnancy loss.
• To analyze trios (mother, father, fetus) from clinically diagnosed pregnancy loss cases.

Main Methods:

• Whole-genome sequencing (WGS) of 664 early pregnancy loss cases (1439 fetal samples, 467 trios).
• Assessment of aneuploidies, de novo copy number variants (CNVs), and single-site variants (SSVs).
• Analysis of mutation origins (paternal vs. maternal) and recombination failure.

Main Results:

• Aneuploidies detected in 206 cases (most common: monosomy X, trisomy 16).
• 19 large de novo CNVs identified in 14 cases.
• Pathogenic or likely pathogenic SSVs found in 26 genotypes, with higher frequency in early pregnancy loss compared to controls.
• Probable genetic causes identified in 254 of 467 cases.
• Most genetic causes originated on maternal chromosomes.
• Triploid fetuses had significantly more DNMs than euploid fetuses.
• High paternal contribution to DNMs confirmed, with specific patterns in triploidies.

Conclusions:

• Significant sequence diversity contributes to early pregnancy loss.
• Genetic factors, including aneuploidies, triploidies, pathogenic SSVs, and de novo CNVs, explain a substantial portion of early pregnancy loss.
• Most identified genetic causes originate on maternal chromosomes.
• Further research is needed for non-genetic causes and potential interventions.