DLL1 has been reported in relation to autosomal dominant neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (NEDBAS) (Fischer-Zirnsak et al. 2019, PMID: 31353024). NEDBAS is a highly variable syndrome characterized by impaired intellectual development and behavioral abnormalities associated with structural changes in brain imaging. Note: there have been reports of individuals with holoprosencephaly and either copy number variants including DLL1 (in addition to other genes) or single nucleotide variants in DLL1 (along with other variants in other holoprosencephaly genes). This information is not being considered as part of this curation.
Five frameshift, four nonsense, two missense, and one indel variants that have been reported in 12 probands in 2 publications (PMIDs:31353024, 37204857) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity has been shown to be haploinsufficiency. This gene-disease relationship is also supported by mouse models (PMIDs: 23695674, 36590296). In summary, there is definitive evidence supporting the relationship between DLL1 and autosomal dominant neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date April 23rd, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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