Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Am J Hum Genet. 2019 Sep 5;105(3):631-639. doi: 10.1016/j.ajhg.2019.07.002. Epub 2019 Jul 25.


Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.

Keywords: DLL1; Notch signaling; autism; brain malformation; developmental delay; intellectual disability; vertebral segmentation defects.

Publication types

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

MeSH terms

  • Calcium-Binding Proteins / genetics*
  • Cohort Studies
  • Exome Sequencing
  • Female
  • Haploinsufficiency*
  • Humans
  • Ligands
  • Male
  • Membrane Proteins / genetics*
  • Neurodevelopmental Disorders / genetics*
  • Pedigree


  • Calcium-Binding Proteins
  • DLK1 protein, human
  • Ligands
  • Membrane Proteins