Risk of meningomyelocele mediated by the common 22q11.2 deletion

Science. 2024 May 3;384(6695):584-590. doi: 10.1126/science.adl1624. Epub 2024 May 2.

Abstract

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 22* / genetics
  • DiGeorge Syndrome / genetics
  • Exome Sequencing
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid Deficiency / complications
  • Folic Acid Deficiency / genetics
  • Humans
  • Male
  • Meningomyelocele* / epidemiology
  • Meningomyelocele* / genetics
  • Mice
  • Penetrance
  • Risk
  • Spinal Dysraphism / genetics

Substances

  • Folic Acid
  • CRKL protein
  • Adaptor Proteins, Signal Transducing