Should Exome Sequencing Replace Chromosomal Microarray Analysis in Suspected Skeletal Dysplasias? Lessons from a Case...

Skeletal dysplasias are genetically heterogeneous disorders characterized by high diagnostic complexity and major perinatal impact. Under current diagnostic guidelines, chromosomal microarray remains the recommended first-tier test for fetal anomalies. However, in suspected skeletal dysplasias ‑ where sequencing provides a markedly higher diagnostic yield ‑ starting with chromosomal microarray testing may delay diagnosis. Recent advances in next-generation sequencing, along with the 2022 International Society of Skeletal Dysplasias classification, now allow for earlier and more precise evaluation. We present a case of life-limiting osteogenesis imperfecta diagnosed prenatally through exome sequencing (ES), highlighting its efficiency and diagnostic advantage over chromosomal microarray analysis.

A 24-year-old primigravida was assessed during first trimester screening in Cartagena, Colombia. Ultrasound at 13 weeks revealed multiple fetal anomalies suggestive of skeletal dysplasia. Chorionic villus sampling was performed, and molecular analysis with ES identified a heterozygous substitution NM_000088.3:c.1291G>T (p.Gly431Cys) in COL1A1, located in the triple helix domain of type I collagen. This variant was absent from genomic databases and showed previously documented glycine substitutions, being classified as "likely pathogenic." The patient opted for legal termination of pregnancy, and fetal histopathology confirmed osteogenesis imperfecta.

This novel COL1A1 variant reinforces the role of glycine substitutions in osteogenesis imperfecta. While chromosomal microarray remains first-tier, ES offers a faster and more efficient pathway for diagnosing suspected skeletal dysplasias, enhancing early counseling in resource-limited settings.