Genomic Exploration of Severe Mendelian Developmental Anomalies: Insights From Exome Sequencing Analyses in a Large Indian Cohort

Objectives To evaluate the diagnostic utility of exome sequencing (ES) in structurally abnormal fetuses and infants with suspected severe Mendelian developmental defects. Methods This retrospective study included fetuses (≥ 12 weeks) and infants (≤ 6 months old) with suspected severe Mendelian disorders, clinically categorized as multiple malformations (MM), non‐immune hydrops (NIH), and skeletal dysplasia (SKD). All subjects underwent detailed evaluation by a clinical geneticist, which included a clinical examination or fetal autopsy, as applicable, with parental consent. Based on the type of anomaly, investigations such as karyotype, chromosomal microarray (CMA), and/or proband exome sequencing (ES) were performed. Results Ninety‐seven unrelated subjects were enrolled, including 25 (25.8%) multiplex and 17 (17.5%) consanguineous families. They were categorized as multiple malformations (MM) (60/97), skeletal dysplasia (SKD) (19/97), and non‐immune hydrops (NIH) (18/97), respectively. The CMA performed in 23 subjects was normal. The overall diagnostic yield of ES for pathogenic/likely pathogenic variants was 40.2% (39/97) and was higher in SKD (57.9%, 11/19), followed by NIH (44.4%, 8/18) and MM (33.3%, 20/60). Eighteen novel variants were identified in 16 genes in various categories. Additional findings on fetal autopsy helped in making a precise diagnosis in 8/21 (38%) subjects. Conclusion This study elucidates the molecular basis of severe Mendelian developmental defects in early life. Proband‐only ES helps in reaching a precise diagnosis in combination with deep phenotyping using fetal autopsy and has a good diagnostic yield. It could be used as a first‐tier test, especially in resource‐poor settings.