Screening of triploid in miscarriage tissues using medium-coverage whole genome sequencing with a three-algorithm...

Area of Science:

• Genomics
• Reproductive Medicine
• Prenatal Diagnostics

Background:

• Triploidy is a common chromosomal abnormality in early pregnancy miscarriages.
• Accurate detection of triploidy is crucial for genetic counseling and understanding reproductive outcomes.
• Existing methods like chromosomal microarray analysis (CMA) and low-coverage whole genome sequencing (CNV-seq) have limitations.

Purpose of the Study:

• To evaluate the effectiveness and accuracy of medium-coverage whole genome sequencing (CMA-seq) for detecting triploidy in miscarriage tissues.
• To compare CMA-seq performance against CMA and CNV-seq combined with short tandem repeat (STR) testing.

Main Methods:

• Validated CMA-seq using four triploid miscarriage samples.
• Employed three algorithms: X/Y chromosome dosage ratio, SNP-based variant allele frequency (VAF) modeling, and CNV segmentation.
• Applied the validated CMA-seq pipeline to 38 miscarriage samples previously characterized by CMA or CNV-seq/STR.

Main Results:

• CMA-seq accurately identified triploid subtypes (69,XXY, 69,XXX, 69,XYY) during validation.
• Achieved 100% concordance with CMA in 23 samples and 100% agreement with CNV-seq/STR in 15 samples.
• Demonstrated distinct VAF profiles and fractional copy number states for triploid samples.

Conclusions:

• CMA-seq, with its integrated algorithmic framework, is a robust and sensitive method for triploidy detection in miscarriage tissues.
• Provides detailed genomic profiles that can enhance clinical decision-making.
• Supports improved genetic counseling for affected families.