DLL1

Gene Facts

• HGNC Symbol: DLL1 (HGNC:2908)
• HGNC Name: delta like canonical Notch ligand 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: No aliases found
• %HI: 4.66
• pLI: 1
• LOEUF: 0.24
• Cytoband: 6q27
• Genomic Coordinates:

  GRCh37/hg19:	chr6:170591294-170600166
  GRCh38/hg38:	chr6:170282206-170291078

• MANE Select Transcript: NM_005618.4 ENST00000366756.4
• Function: Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-22525
• ClinGen Curation ID: CCID:007000
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 03/09/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures

HI Evidence

• PUBMED: 31353024
  Fischer-Zirnsak et al (2019) identified 15 individuals from 12 families from Matchmaker Exchange with DLL1 gene disrupting variants (following exome sequencing). Most common features in the cohort were intellectual disability (12/14), variable brain malformations (11/15), autism spectrum disorder (6/14) and seizures (6/14). 5 with de novo nonsense variants 2 with segregation from an affected parent (mother to 3 children; father to child) 1 with a de novo deletion that also included FAM120B (this gene has pLI = 0; whereas DLL1 =1) 1 with a de novo missense (at a highly conserved position) 3 with nonsense variants but parents untested The authors note phenotypic overlap with 6q27 deletion syndrome; this gene is in 6q27. There is an association of DLL1 haploinsufficiency with holoprosencephaly in the literature but the findings here and in gnomAD (previously identified variants in holoprosencephaly cohorts have been identified at high population frequencies) suggest that this should be re-evaluated. DLL1 is a ligand for the Notch receptor and 3 other Notch ligands have been associated with human monogenic diseases: monoallelic pathogenic variants in JAG1 (MIM: 601920) causing Alagille syndrome 1 (MIM: 118450) and tetralogy of Fallot (MIM: 187500), monoallelic pathogenic variants in DLL4 (MIM: 605185) causing Adams-Olliver syndrome 6 (MIM: 616589), and biallelic pathogenic variants in DLL3 (MIM: 602768) causing spondylocostal dysostosis 1 (MIM: 602768). DLL1 was one of the few Notch signalling genes that wasn't already associated with a genetic disorder at time of a review being written in 2017 (PMID 28512196).
• PUBMED: 22542183
  Iossifov et al (2012) carried out exome sequencing of 343 autism families: 1 de novo DLL1 disrupting (dupT -> fs) variant.

• HI Evidence Comments: There are a number of reports of 6q27 deletion syndrome, which includes this gene. It has been suggested that DLL1 may be key to the brain malformation phenotypes observed (Hanna et al 2019, PMID 31602192; Thakur et al 2018, PMID 30194807).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity