Causal Genetic Variants in Stillbirth.

Area of Science:

• Genomics
• Medical Genetics
• Reproductive Medicine

Background:

• The cause of stillbirth is often unknown despite extensive evaluation.
• Chromosomal abnormalities account for 10-20% of stillbirths.
• The role of small exonic variants in stillbirth etiology is understudied.

Purpose of the Study:

• To investigate the diagnostic utility of exome sequencing in stillbirth.
• To identify causal small genomic variants in stillborn infants.
• To assess the contribution of variation in gene intolerance to stillbirth.

Main Methods:

• Exome sequencing data generated for 246 stillborn cases.
• Application of guidelines to identify causal variants in known and candidate disease genes.
• Case-control analysis of 18,653 genes stratified by variation intolerance.

Main Results:

• Molecular diagnoses were identified in 6.1% (15/246) of stillbirth cases.
• Identified variants involved seven previously implicated and six candidate stillbirth genes.
• Enrichment of loss-of-function variants in variation-intolerant genes was observed (OR 2.15), particularly in novel disease genes (OR 2.22).

Conclusions:

• Clinical exome sequencing is valuable for diagnosing stillbirth cases with small genomic changes.
• The genetic causes of stillbirth remain largely unidentified, with novel risk signals emerging.
• Findings suggest a significant role for variants in previously unassociated, intolerance-to-variation genes.