Exome sequencing uncovers promising candidate genes for foetal structural malformations.

Background & objectives Prenatal ultrasonography in the first and second trimesters detects foetal structural anomalies in up to five per cent of pregnancies. These anomalies are often suspected to have a genetic cause. While conventional genetic tests such as karyotyping, fluorescent in situ hybridisation (FISH), and chromosomal microarray (CMA) have been used alongside whole-exome sequencing (WES), their combined diagnostic yield in malformed foetuses is limited to 40 per cent, leaving most cases undiagnosed. This study aimed to identify novel genetic factors linked to foetal structural malformations. Methods A total of 44 medically terminated foetuses were included in this study with severe structural malformations from a maternity hospital in the western part of India. We performed a comprehensive genetic analysis of products of conception (POC) employing karyotyping, FISH, CMA (750K resolution) and WES. Further, in cases with inconclusive genetic findings, we reanalysed the WES data using our in-house analysis pipeline and Exomiser (v13.2.1). Results Genetic anomalies identified among the 44 foetuses included trisomy 21 (n=4), trisomy 13 (n=3), and XXY mosaicism 47 (n=1) in 18.1 per cent (8 out of 44) of the cases. Further, CMA identified CNVs in 13.6 per cent (n=6) cases, of which five cases showed pathogenic CNVs. With the inclusion of WES, the diagnostic yield increased by 4.5 per cent. We reanalysed the WES data and identified six potential candidates, including RUNX2 (spinal dysraphism), PALLD (Arnold-Chiari malformation), KMT2D (Holoprosencephaly), FBN2 (structural heart and spine defects), CPLANE1 (Dandy-Walker malformation), and KMD1A (structural brain abnormality). Interpretation & conclusions This study summarises the findings of genetic evaluation of malformed foetuses in a low-resource setting, which caters to low-income groups of society. The candidate genes reported in this study offer scope for functional studies in relevant animal models to establish genotype-phenotype correlation.