Whole-Exome Sequencing Boosts Diagnostic Yield to 36.3 percent in Fetal Anomalies: New IJMR Study Finds

While prenatal ultrasonography (USG) identifies developmental defects in up to five percent of pregnancies, conventional tools such as karyotyping, fluorescent in situ hybridization (FISH), and chromosomal microarray (CMA) frequently leave the genetic etiology of these anomalies unresolved; consequently, Digumarthi V.S. Sudhakar and colleagues of the ICMR-National Institute for Research in Reproductive and Child Health conducted the research to address the clinical gap in characterizing monogenic causes of lethal fetal malformations by employing a comprehensive genomic strategy to identify novel candidate genes.

Therefore, the prospective investigation, conducted from October 2021 to May 2023 at a maternity hospital in Mumbai, utilized WES alongside karyotyping, FISH, and CMA to analyze 44 medically terminated fetuses presenting with severe syndromic and non-syndromic anomalies, while meticulously excluding cases related to placental pathology or maternal risk to ensure that variant prioritization via in-house pipelines and cross-species comparisons accurately targeted primary and secondary genetic endpoints.

Key Findings of the Study Include:

• Aneuploidy Detection: The study confirmed that standard chromosomal analysis successfully identified trisomies 21 and 13, along with XXY mosaicism, in 18.1 percent of the malformed fetuses.

• CNV Identification: Utilizing chromosomal microarray, researchers identified pathogenic copy number variations (CNVs) in 11.4 percent of cases, including a significant de novo 17p11.2 variation that presented as distinct heart or skeletal defects depending on the gain or loss of genetic material.

• Exome Diagnostic Yield: The investigation found that the addition of WES provided a conclusive diagnosis in 4.5 percent of previously undiagnosed cases by pinpointing pathogenic variants in the ASPM and SPECC1L genes.

• Candidate Gene Discovery: Through sophisticated phenotype-driven reanalysis, the study proposed six potential candidate genes, including PALLD for neural tube defects and RUNX2 for spinal dysraphism, highlighting genes that cause embryonic lethality in animal models but remain under-characterized in human prenatal medicine.

• Cumulative Diagnostic Success: By integrating all genetic testing modalities, the researchers achieved a total conclusive diagnosis in 16 out of 44 cases (36.3%), proving that a tiered multi-modal approach significantly enhances the detection of monogenic fetal anomalies.

The results suggest that WES is an invaluable discovery tool for identifying novel genetic causes of FSAs, as it successfully increased the diagnostic yield by 4.5 percent and identified variants of unknown significance in another 4.5 percent of the study cohort.

The study concludes that clinicians can apply these findings to offer more precise perinatal management and provide families with essential guidance regarding recurrence risk and genetic counselling for future pregnancies.

While the study was limited by a relatively small sample size and the absence of detailed fetal autopsy data, it underscores an attractive opportunity for future large-scale systemic genomic research to further elucidate the complex roles of specific genes during embryogenesis.

Reference

Sudhakar DVS, Joseph S, Bansal V, Gangurde A, Minde NN, Gawde H, et al. Exome sequencing uncovers promising candidate genes for foetal structural malformations. Indian J Med Res. 2025;161(5):510-520.