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

To evaluate the diagnostic utility of exome sequencing (ES) in structurally abnormal fetuses and infants with suspected severe Mendelian developmental defects.

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.

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.

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.