Association between rare variants in specific functional pathways and human neural tube defects multiple...

Area of Science:

• Genetics
• Developmental Biology
• Neuroscience

Background:

• Neural tube defects (NTDs) are congenital abnormalities resulting from failed neural tube closure, presenting diverse central nervous system phenotypes.
• While mouse models offer insights, the genetic associations with human NTD subphenotypes remain poorly understood.

Purpose of the Study:

• To investigate the genetic underpinnings of human NTDs by exploring associations between gene variants and specific NTD subphenotypes.
• To identify biological functions and pathways implicated in the pathogenesis of different NTD presentations.

Main Methods:

• Targeted genome DNA sequencing of 280 neural tube closure-related genes was conducted.
• Analysis included 355 NTD cases and 225 ethnicity-matched controls.

Main Results:

• Potentially damaging rare variants in genes involved in chromatin modification, apoptosis, retinoid metabolism, and lipid metabolism are associated with human NTDs.
• Specific NTD phenotypes showed associations with distinct biological functions: anencephaly (chromatin modification), encephalocele (apoptosis, retinoid/one carbon metabolism), spina bifida aperta/cystica (apoptosis), and spina bifida occulta (lipid metabolism).
• Craniorachischisis is linked to chromatin modification and retinoid metabolism, beyond the planar cell polarity pathway.

Conclusions:

• This research establishes a link between genetic variants and human NTD subphenotypes.
• The findings provide crucial preliminary evidence for investigating the pathogenic mechanisms underlying various NTDs.