Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects

Area of Science:

• Developmental Biology
• Human Genetics
• Molecular Biology

Background:

• Neural tube defects (NTDs) are severe congenital abnormalities with largely unknown human genetic causes.
• While mouse models implicate various pathways, human genetic factors for NTDs remain elusive.

Observation:

• Whole exome sequencing identified deleterious variants in crucial apoptotic genes in two families experiencing recurrent NTDs.
• Functional studies using fibroblasts demonstrated these variants result in loss-of-function, significantly impairing apoptosis.

Findings:

• This research is the first to report human variants in apoptotic genes associated with NTD risk.
• Identified loss-of-function variants in apoptotic genes disrupt programmed cell death, contributing to NTD development.

Implications:

• Uncovers a novel molecular mechanism underlying human NTDs, focusing on apoptosis regulation.
• Highlights the importance of investigating apoptotic gene variants in sporadic and familial NTD cases.
• Opens new avenues for understanding NTD etiology and potential therapeutic targets.