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Relevance to Autism

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Molecular Function

Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Also involved in secretory granule priming in insulin secretion.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.
ASD, ADHD, DD, dyskinetic movement disorder
Support
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.
DD
Support
Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.
ASD
Support
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
DD, epilepsy/seizures, microcephaly
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.
ASD
Support
The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing
ASD
Recent Recommendation
A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN869R001 
 missense_variant 
 c.2441C>T 
 p.Pro814Leu 
 De novo 
 NA 
 Simplex 
 GEN869R002 
 missense_variant 
 c.3428C>A 
 p.Ala1143Glu 
 De novo 
 NA 
  
 GEN869R003a 
 splice_site_variant 
 c.4197+7C>T 
  
 Familial 
 Both parents 
 Multiplex 
 GEN869R004a 
 missense_variant 
 c.154G>A 
 p.Glu52Lys 
 Unknown 
  
  
 GEN869R005 
 stop_gained 
 c.4781G>A 
 p.Trp1594Ter 
 De novo 
 NA 
 Simplex 
 GEN869R006 
 missense_variant 
 c.4379C>T 
 p.Ala1460Val 
 De novo 
 NA 
 Unknown 
 GEN869R007 
 inframe_insertion 
 c.1082_1083insAGGAGG 
 p.Arg361_Glu362insGlyGly 
 Unknown 
  
 Unknown 
 GEN869R008 
 splice_region_variant 
 c.4197+7C>T 
  
 Familial 
  
  
 GEN869R009 
 frameshift_variant 
 c.1800del 
 p.Asn600LysfsTer32 
 Familial 
  
  
 GEN869R010 
 missense_variant 
 ENSG00000130477:ENST00000552293:exon20:c.G2425A:p.E809K,ENSG00000130477:ENST00000428389:exon21:c.G26 
  
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion-Duplication
 16
 
19
Duplication
 1
 
19
Duplication
 1
 
19
Duplication
 1
 
19
Duplication
 1
 

No Animal Model Data Available

No PIN Data Available
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