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Relevance to Autism

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Additional de novo loss-of-function and missense variants in the SRCAP gene were observed in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; furthermore, a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified SRCAP as a gene reaching exome-wide significance (P < 2.5E-06). Rots et al., 2021 reported 33 unrelated individuals with truncating SRCAP variants proximal (n=28) or distal (n=5) to the locus for Floating-Harbor syndrome who presented with a distinct neurodevelopmental disorder characterized by developmental delay with or without intellectual disability, behavioral and psychiatric abnormalities, non-specific facial features, musculoskeletal abnormalities, and hypotonia; autism spectrum disorder was observed in individuals with both proximal SRCAP variants (10/24; 41.67%) and distal SRCAP variants (2/5; 40%) in this report.

Molecular Function

This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome (OMIM 136140), a rare disorder characterized by short stature, language deficits and dysmorphic facial features.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Microcephaly
Support
ASD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
DD, ID
Stereotypy
Support
Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability
ID
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
ASD
DD, ID, epilepsy/seizures
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Recent Recommendation
Integrating de novo and inherited variants in 42
ASD
Recent Recommendation
Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature
DD
ASD, ADHD, ID
Recent Recommendation
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN871R001 
 frameshift_variant 
 c.6409del 
 p.Asp2137ThrfsTer41 
 De novo 
  
 Simplex 
 GEN871R002 
 missense_variant 
 c.7002G>C 
 p.Gln2334His 
 De novo 
  
  
 GEN871R003 
 missense_variant 
 c.5809G>A 
 p.Gly1937Ser 
 De novo 
  
 Simplex 
 GEN871R004 
 missense_variant 
 c.5179A>T 
 p.Thr1727Ser 
 De novo 
  
 Simplex 
 GEN871R005 
 splice_site_variant 
 c.2494-2A>G 
  
 De novo 
  
 Simplex 
 GEN871R006 
 missense_variant 
 c.450C>G 
 p.Asp150Glu 
 De novo 
  
  
 GEN871R007 
 frameshift_variant 
 c.5972_5975del 
 p.His1991ProfsTer44 
 De novo 
  
 Simplex 
 GEN871R008 
 splice_site_variant 
 c.3893-2A>G 
  
 De novo 
  
  
 GEN871R009 
 frameshift_variant 
 c.1143_1153delinsTGT 
 p.Pro382ValfsTer14 
 Unknown 
 Not maternal 
  
 GEN871R010 
 frameshift_variant 
 c.1608_1611delinsCA 
 p.Gln537LysfsTer5 
 De novo 
  
  
 GEN871R011 
 stop_gained 
 c.6208C>T 
 p.Arg2070Ter 
 De novo 
  
  
 GEN871R012 
 frameshift_variant 
 c.5984del 
 p.Pro1995HisfsTer41 
 Familial 
 Paternal 
  
 GEN871R013 
 splice_site_variant 
 c.55-1G>A 
  
 De novo 
  
  
 GEN871R014 
 stop_gained 
 c.1174C>T 
 p.Gln392Ter 
 De novo 
  
  
 GEN871R015 
 frameshift_variant 
 c.5461delinsAGA 
 p.Ser1821ArgfsTer32 
 De novo 
  
  
 GEN871R016 
 frameshift_variant 
 c.5102_5103del 
 p.Ser1701PhefsTer146 
 Familial 
 Maternal 
  
 GEN871R017 
 frameshift_variant 
 c.4648del 
 p.Val1550CysfsTer34 
 De novo 
  
  
 GEN871R018 
 frameshift_variant 
 c.4557_4560del 
 p.Gln1519HisfsTer18 
 De novo 
  
  
 GEN871R019 
 stop_gained 
 c.2518C>T 
 p.Arg840Ter 
 De novo 
  
  
 GEN871R020 
 frameshift_variant 
 c.6901del 
 p.Glu2301LysfsTer6 
 De novo 
  
  
 GEN871R021 
 frameshift_variant 
 c.5633dupC 
 p.Pro1879ThrfsTer21 
 Unknown 
 Not maternal 
  
 GEN871R022 
 frameshift_variant 
 c.5633dupC 
 p.Pro1879ThrfsTer21 
 De novo 
  
  
 GEN871R023 
 frameshift_variant 
 c.1793del 
 p.Gly598ValfsTer9 
 De novo 
  
  
 GEN871R024 
 frameshift_variant 
 c.5527del 
 p.Val1843PhefsTer9 
 Unknown 
  
  
 GEN871R025 
 frameshift_variant 
 c.5977_5980del 
 p.Cys1993ThrfsTer42 
 De novo 
  
  
 GEN871R026 
 stop_gained 
 c.3833C>A 
 p.Ser1278Ter 
 De novo 
  
  
 GEN871R027 
 frameshift_variant 
 c.5633dup 
 p.Pro1879ThrfsTer21 
 De novo 
  
  
 GEN871R028 
 frameshift_variant 
 c.833del 
 p.Pro278LeufsTer102 
 De novo 
  
  
 GEN871R029 
 stop_gained 
 c.4925T>A 
 p.Leu1642Ter 
 De novo 
  
  
 GEN871R030 
 frameshift_variant 
 c.5549_5556del 
 p.Thr1850IlefsTer47 
 De novo 
  
  
 GEN871R031 
 frameshift_variant 
 c.5387del 
 p.Pro1796LeufsTer56 
 De novo 
  
  
 GEN871R032 
 frameshift_variant 
 c.148del 
 p.His50ThrfsTer2 
 De novo 
  
  
 GEN871R033 
 frameshift_variant 
 c.6889del 
 p.Arg2297GlyfsTer10 
 De novo 
  
  
 GEN871R034 
 frameshift_variant 
 c.435del 
 p.Gln145HisfsTer25 
 De novo 
  
  
 GEN871R035 
 frameshift_variant 
 c.4200_4204del 
 p.Leu1401ArgfsTer23 
 De novo 
  
  
 GEN871R036 
 frameshift_variant 
 c.8592dup 
 p.Lys2865GlnfsTer15 
 Unknown 
 Not paternal 
  
 GEN871R037 
 frameshift_variant 
 c.9126dup 
 p.Gln3043AlafsTer9 
 De novo 
  
  
 GEN871R038 
 frameshift_variant 
 c.9338_9341del 
 p.Leu3113ProfsTer14 
 Unknown 
  
  
 GEN871R039 
 frameshift_variant 
 c.9364del 
 p.Leu3122CysfsTer6 
 Unknown 
 Not maternal 
  
 GEN871R040 
 frameshift_variant 
 c.9344del 
 p.Pro3115GlnfsTer13 
 De novo 
  
  
 GEN871R041 
 missense_variant 
 c.6805G>A 
 p.Ala2269Thr 
 Unknown 
  
  
 GEN871R042 
 frameshift_variant 
 c.7275_7282dup 
 p.Arg2428HisfsTer50 
 De novo 
  
  
 GEN871R043 
 splice_site_variant 
 c.2494-2A>G 
  
 De novo 
  
  
 GEN871R044 
 missense_variant 
 c.5293G>C 
 p.Ala1765Pro 
 De novo 
  
  
 GEN871R045 
 missense_variant 
 c.6451C>T 
 p.Arg2151Cys 
 De novo 
  
  
 GEN871R046 
 missense_variant 
 c.9361C>T 
 p.Arg3121Trp 
 De novo 
  
  
 GEN871R047 
 missense_variant 
 c.5821C>T 
 p.Pro1941Ser 
 De novo 
  
 Simplex 
 GEN871R048 
 missense_variant 
 c.8381G>A 
 p.Arg2794His 
 De novo 
  
 Simplex 
 GEN871R049 
 synonymous_variant 
 c.282C>T 
 p.Ala94%3D 
 De novo 
  
  
 GEN871R050 
 missense_variant 
 c.1799C>T 
 p.Thr600Met 
 De novo 
  
  
 GEN871R051 
 frameshift_variant 
 c.7488_7489insG 
 p.Pro2497AlafsTer46 
 De novo 
  
  
 GEN871R052 
 missense_variant 
 c.8984C>G 
 p.Thr2995Ser 
 De novo 
  
  
 GEN871R053 
 missense_variant 
 c.9361C>T 
 p.Arg3121Trp 
 De novo 
  
  
 GEN871R054 
 frameshift_variant 
 c.5161del 
 p.Ala1721HisfsTer48 
 De novo 
  
  
 GEN871R055 
 frameshift_variant 
 c.5258del 
 p.Pro1753LeufsTer16 
 De novo 
  
  
 GEN871R056 
 missense_variant 
 c.7028G>C 
 p.Arg2343Pro 
 De novo 
  
  
 GEN871R057 
 frameshift_variant 
 c.7096_7102del 
 p.Ala2366MetfsTer107 
 De novo 
  
  
 GEN871R058 
 missense_variant 
 c.8388G>A 
 p.Met2796Ile 
 De novo 
  
  
 GEN871R059 
 missense_variant 
 c.8975C>T 
 p.Thr2992Ile 
 De novo 
  
  
 GEN871R060 
 stop_gained 
 c.7330C>T 
 p.Arg2444Ter 
 De novo 
  
  
 GEN871R061 
 missense_variant 
 c.4628C>T 
 p.Pro1543Leu 
 Familial 
 Paternal 
  
 GEN871R062 
 missense_variant 
 c.4451T>A 
 p.Val1484Asp 
 Familial 
 Maternal 
  
 GEN871R063 
 stop_gained 
 c.1849C>T 
 p.Gln617Ter 
 De novo 
  
  
 GEN871R064 
 missense_variant 
 c.6710A>C 
 p.Gln2237Pro 
 Familial 
 Paternal 
 Simplex 
 GEN871R065 
 stop_gained 
 c.7300G>T 
 p.Glu2434Ter 
 Unknown 
  
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Deletion-Duplication
 139
  construct
16
Deletion
 1
 
16
Deletion
 1
 

Model Summary

dom mutants showed a habituation deficit.

References

Type
Title
Author, Year
Primary
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

F_DOM_1_KD_GAL4:UAS;RNAI-VDRC7787

Model Type: Genetic
Model Genotype: Wild type
Mutation: dom-Gal4 driver line expressing UAS-dom-RNAi.
Allele Type: Loss-of-function
Strain of Origin: Not reported
Genetic Background: Not reported
ES Cell Line:
Mutant ES Cell Line:
Model Source:

F_DOM_1_KD_GAL4:UAS;RNAI-VDRC7787

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Habituation to aversive stimuli1
Decreased
Description: When challenged in the light-off jump paradigm, the mutants showed a habituation deficit compared to controls.
Exp Paradigm: Habituation was measured in number of trials to reach no-jump criterion.
 Light-off startle jump
 adult stage
Startle response1
 No change
 Light-off startle jump
 adult stage
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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