Human Gene Module / Chromosome 6 / DLL1

DLL1delta like canonical Notch ligand 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
19 / 0
Aliases
DLL1, DELTA1,  DL1,  Delta
Associated Syndromes
-
Chromosome Band
6q27
Associated Disorders
ASD, EPS
Relevance to Autism

A de novo frameshift variant in the DLL1 gene was identified in an ASD proband from the Simons Simplex Collection in O'Roak et al., 2014. Fischer-Zirnsak et al., 2019 identified 15 individuals from 12 unrelated families with heterozygous and likely pathogenic DLL1 variants; the most common phenotypes observed in this cohort were developmental delay/intellectual disability (12/14), autism spectrum disorder (6/14), seizures (6/14), muscular hypotonia (6/14), abnormal brain MRI (11/15), and facial dysmorphism (8/15).

Molecular Function

DLL1 is a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family. It plays a role in mediating cell fate decisions during hematopoiesis. It may play a role in cell-to-cell communication.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DLL1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
2 Recent Recommendation Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders Fischer-Zirnsak B , et al. (2019) No ASD, epilepsy/seizures, hypotonia, abnormal brain
3 Support - Woodbury-Smith M et al. (2022) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Tuncay IO et al. (2023) Yes -
6 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.619C>T p.Arg207Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss De novo - Simplex 31353024 Fischer-Zirnsak B , et al. (2019)
c.1957G>A p.Ala653Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1881C>T p.Ala627= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.422A>G p.Glu141Gly missense_variant De novo - - 37492102 Tuncay IO et al. (2023)
c.54+1G>A - splice_site_variant De novo - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.1492G>T p.Glu498Ter stop_gained De novo - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.503G>C p.Arg168Pro missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1336G>A p.Asp446Asn missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.536G>T p.Cys179Phe missense_variant De novo - Simplex 31353024 Fischer-Zirnsak B , et al. (2019)
c.1291dup p.Cys431LeufsTer11 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.50_51del p.Cys17SerfsTer108 frameshift_variant Unknown - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.231C>A p.Cys77Ter stop_gained Familial Maternal Multiplex 31353024 Fischer-Zirnsak B , et al. (2019)
c.2013_2014del p.Glu673GlyfsTer15 frameshift_variant Unknown - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.1401_1402insCACCT p.Thr468HisfsTer71 frameshift_variant De novo - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.54_54+1insTAGTCG p.Gln18_Val19insTer splice_site_variant De novo - - 31353024 Fischer-Zirnsak B , et al. (2019)
c.2013_2014del p.Glu673GlyfsTer15 frameshift_variant De novo - Simplex 31353024 Fischer-Zirnsak B , et al. (2019)
c.1525C>T p.Arg509Ter stop_gained Familial Paternal Multi-generational 31353024 Fischer-Zirnsak B , et al. (2019)
c.543_544insACACTACTACGGAGAGGGCTGCTCCGTT p.His182ThrfsTer59 frameshift_variant Unknown Not maternal Multi-generational 31353024 Fischer-Zirnsak B , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo frameshift variant in the DLL1 gene was identified in an ASD proband from the Simons Simplex Collection in O'Roak et al., 2014. Fischer-Zirnsak et al., 2019 identified 15 individuals from 12 unrelated families with heterozygous and likely pathogenic DLL1 variants; the most common phenotypes observed in this cohort were developmental delay/intellectual disability (12/14), autism spectrum disorder (6/14), seizures (6/14), muscular hypotonia (6/14), abnormal brain MRI (11/15), and facial dysmorphism (8/15).

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo frameshift variant in the DLL1 gene was identified in an ASD proband from the Simons Simplex Collection in O'Roak et al., 2014. Fischer-Zirnsak et al., 2019 identified 15 individuals from 12 unrelated families with heterozygous and likely pathogenic DLL1 variants; the most common phenotypes observed in this cohort were developmental delay/intellectual disability (12/14), autism spectrum disorder (6/14), seizures (6/14), muscular hypotonia (6/14), abnormal brain MRI (11/15), and facial dysmorphism (8/15).

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo frameshift variant in the DLL1 gene was identified in an ASD proband from the Simons Simplex Collection in O'Roak et al., 2014. Fischer-Zirnsak et al., 2019 identified 15 individuals from 12 unrelated families with heterozygous and likely pathogenic DLL1 variants; the most common phenotypes observed in this cohort were developmental delay/intellectual disability (12/14), autism spectrum disorder (6/14), seizures (6/14), muscular hypotonia (6/14), abnormal brain MRI (11/15), and facial dysmorphism (8/15).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
4S

Increased from to 4S

Description

A de novo frameshift variant in the DLL1 gene was identified in an ASD proband from the Simons Simplex Collection in O'Roak et al., 2014. Fischer-Zirnsak et al., 2019 identified 15 individuals from 12 unrelated families with heterozygous and likely pathogenic DLL1 variants; the most common phenotypes observed in this cohort were developmental delay/intellectual disability (12/14), autism spectrum disorder (6/14), seizures (6/14), muscular hypotonia (6/14), abnormal brain MRI (11/15), and facial dysmorphism (8/15).

Krishnan Probability Score

Score 0.49966139322833

Ranking 2143/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99905306743692

Ranking 1058/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.971

Ranking 55/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.50776107859709

Ranking 465/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.12577087467901

Ranking 5621/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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