Aliases: AOS5, AOVD1, TAN1, hN1
Chromosome No: 9
Chromosome Band: 9q34.3
Genetic Category: Rare single gene variant-Functional-Rare single gene variant/Functional
ASD Reports: 10
Recent Reports: 0
Annotated variants: 21
Associated CNVs: 7
Evidence score: 3
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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.
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