Human Gene Module / Chromosome 9 / NOTCH1

NOTCH1notch receptor 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9q34.3
Associated Disorders
-
Relevance to Autism

De novo variants in the NOTCH1 gene have been identified in ASD probands from multiple cohorts, including a de novo nonsense variant, a de novo splice-site variant that was experimentally shown in Li et al., 2023 to result in the insertion of 157 base pairs from intron 31, and several de novo missense variants that were predicted to be damaging (Iossifov et al., 2014; Krumm et al., 2015; Yuen et al., 2017; An et al., 2018; Zhou et al., 2022; Chen et al., 2022). Rare (<1% in gnomAD) and damaging (CADD score > 30) missense variants in NOTCH1 were observed in ASD probands from the Faroe Islands in Leblond et al., 2019, while a nonsense unknown of unknown origin in this gene was reported in a patient from Saudi Arabia presenting with autism, ADHD, speech delay, intellectual disability, and seizure in Alqahtani et al., 2023. NOTCH1 has been shown to interact with the ASD candidate gene NBEA (Tuand et al., 2016); this interaction implicated NBEA as a negative regulator of Notch-mediated transcription.

Molecular Function

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NOTCH1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support - Tuand K , et al. (2016) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
5 Support - Joon-Yong An et al. (2018) Yes -
6 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Chen WX et al. (2022) Yes -
9 Support - Amerh S Alqahtani et al. (2023) Yes -
10 Primary - Kuokuo Li et al. (2024) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.81C>G p.Pro27= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.164C>T p.Pro55Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.237C>T p.Arg79= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2072G>A p.Gly691Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1041C>A p.Gly347= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6311G>A p.Arg2104His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7022C>G p.Ser2341Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4551C>T p.Asp1517= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6018C>T p.Ala2006= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5438G>A p.Trp1813Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5934+5G>C - splice_site_variant De novo - Simplex 30545852 Joon-Yong An et al. (2018)
c.2995G>A p.Val999Met missense_variant De novo - Simplex 36320054 Chen WX et al. (2022)
c.3080C>T p.Ser1027Leu missense_variant De novo - Simplex 36320054 Chen WX et al. (2022)
c.1284G>A p.Lys428= synonymous_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1510C>T p.Arg504Cys missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.7232C>T p.Pro2411Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3468C>T p.Asn1156= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2734C>T p.Arg912Trp missense_variant Unknown - Simplex 30675382 Leblond CS , et al. (2019)
c.3808G>A p.Glu1270Lys missense_variant Unknown - Simplex 30675382 Leblond CS , et al. (2019)
c.2842G>T p.Glu948Ter stop_gained Unknown - Unknown 37799141 Amerh S Alqahtani et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Score Delta: Score remained at 2

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.

4/1/2024
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49488450644395

Ranking 3360/25841 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 0.99999999432062

Ranking 126/18225 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 0.997

Ranking 13/239 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 0.86667504440456

Ranking 4143/18665 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 0.13368922006381

Ranking 5479/20870 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
Submit New Gene

Report an Error