Clinical utility of chromosomal microarray and whole exome sequencing in evaluating genetic causes for pregnancy loss...

To determine the genetic causes of miscarriage by analyzing products of conception (POC).

Chromosomal microarray (CMA) using the Affymetrix Cytoscan HD array was performed in 172 POC specimens from women experiencing spontaneous miscarriage before 20 weeks of gestation to detect aneuploidies, copy number variants (CNVs), and loss of heterozygosity (LOH). Whole exome sequencing (WES) with Roche KAPA HyperExome V2 probes was used for cases where CMA results were normal.

Common clinical indications included recurrent pregnancy loss, first-time miscarriage, absence of cardiac activity, intrauterine death, and fetal growth restriction (FGR), making up 72.55 % of cases. CMA identified chromosomal abnormalities in 38.37 % of samples, with numerical anomalies in 16.86 % and structural anomalies in 21.51 %. Turner syndrome (5.8 %) and various trisomies (5.8 %) were frequent numerical anomalies. Mosaicism and LOH were observed in 11.04 and 2.91 % of cases. WES detected pathogenic or likely pathogenic mutations in 21 genes (e.g., KCNQ1, KCNE1, COL1A2, ROBO1) in 18 cases, adding a 10.46 % diagnostic yield. K-means clustering grouped 17 of these genes into three pathways: chondrocyte differentiation, fibrin clot formation, and Ehlers-Danlos syndrome.

Combining CMA and WES provides a diagnostic yield of 48.83 %, offering a powerful approach to uncover genetic causes of pregnancy loss and guide clinical care.