ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
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).
22542183 Iossifov et al (2012) carried out exome sequencing of 343 autism families: 1 de novo DLL1 disrupting (dupT -> fs) variant.

Haploinsufficiency phenotype 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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity