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Relevance to Autism

Prez Baca et al., 2024 described 42 individuals with protein-truncating variants or deletions of ZFHX3 exhibiting a syndromic form of intellectual disability characterized by global developmental delay, varying degrees of intellectual disability, behavioral problems (including nine individuals with autism spectrum disorder), hypotonia, recurrent facial features, postnatal growth retardation, and brachydactyly; ZFHX3 haploinsufficiency was found to associate with a specific methylation profile in whole blood extracted DNA. Furthermore, Prez Baca et al., 2024 observed that nuclear abundance of ZFHX3 increased during human brain development and neuronal differentiation and that ZFHX3 interacted with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex and predominantly bound to promoters of genes involved in nervous system development. A number of de novo variants in ZFHX3, including a de novo frameshift variant, have also been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, and the MSSNG cohort, among others (De Rubeis et al., 2014; Iossifov et al., 2014; Hashimoto et al., 2016; Yuen et al., 2017; Lim et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022).

Molecular Function

This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. A heterozygous exonic trinucleotide repeat expansion (GGCn) in this gene has also been associated with spinocerebellar ataxia 4 (SCA4; OMIM 600223) (Wallenius et al., 2024).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
DD, ID
ASD, ADD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Recent ultra-rare inherited variants implicate new autism candidate risk genes
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Spinocerebellar ataxia 4
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Genomic architecture of autism from comprehensive whole-genome sequence annotation
ASD
Support
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1438R001 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R002 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R003 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R004 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R005 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R006 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R007 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R008 
 copy_number_loss 
  
  
 Unknown 
  
  
  et al.  
 GEN1438R009 
 copy_number_loss 
  
  
 Unknown 
  
  
  et al.  
 GEN1438R010 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multiplex 
  et al.  
 GEN1438R011 
 copy_number_loss 
  
  
 Unknown 
 Not maternal 
  
  et al.  
 GEN1438R012 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R013 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R014 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R015 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R016 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R017 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R018 
 copy_number_loss 
  
  
 De novo 
  
  
  et al.  
 GEN1438R019 
 stop_gained 
 c.637C>T 
 p.Gln213Ter 
 Unknown 
  
  
  et al.  
 GEN1438R020 
 frameshift_variant 
 c.-23-7459_-23-7456del 
  
 De novo 
  
 Simplex 
  et al.  
 GEN1438R021 
 stop_gained 
 c.1777G>T 
 p.Glu593Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R022 
 stop_gained 
 c.2184C>A 
 p.Cys728Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R023 
 frameshift_variant 
 c.-23-6923del 
  
 De novo 
  
 Simplex 
  et al.  
 GEN1438R024 
 frameshift_variant 
 c.2287dup 
 p.Glu763GlyfsTer26 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R025 
 frameshift_variant 
 c.-5del 
  
 De novo 
  
 Simplex 
  et al.  
 GEN1438R026 
 frameshift_variant 
 c.2876del 
 p.Asp959AlafsTer7 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R027 
 stop_gained 
 c.3355C>T 
 p.Arg1119Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R028 
 stop_gained 
 c.3628C>T 
 p.Arg1210Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R029 
 stop_gained 
 c.3733C>T 
 p.Gln1245Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R030 
 frameshift_variant 
 c.1024dup 
 p.Leu342ProfsTer25 
 Unknown 
 Not maternal 
  
  et al.  
 GEN1438R031 
 frameshift_variant 
 c.1024dup 
 p.Leu342ProfsTer25 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R032 
 frameshift_variant 
 c.4061_4062del 
 p.Val1354GlufsTer28 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R033 
 stop_gained 
 c.4218dup 
 p.Ser1407Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R034 
 frameshift_variant 
 c.4510_4511del 
 p.Ser1504ProfsTer5 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R035 
 stop_gained 
 c.5749G>T 
 p.Glu1917Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R036 
 stop_gained 
 c.6004C>T 
 p.Gln2002Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R037 
 stop_gained 
 c.6040C>T 
 p.Gln2014Ter 
 Familial 
  
 Multi-generational 
  et al.  
 GEN1438R038 
 stop_gained 
 c.6604C>T 
 p.Gln2202Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R039 
 stop_gained 
 c.6827_6828del 
 p.Ser2276Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R040 
 stop_gained 
 c.7660del 
 p.Leu2554Ter 
 De novo 
  
 Simplex 
  et al.  
 GEN1438R041 
 stop_gained 
 c.8002C>T 
 p.Arg2668Ter 
 Unknown 
  
  
  et al.  
 GEN1438R042 
 frameshift_variant 
 c.5962del 
 p.Tyr1988IlefsTer52 
 Unknown 
  
  
  et al.  
 GEN1438R043 
 synonymous_variant 
 c.2370C>T 
 p.Cys790= 
 De novo 
  
  
 GEN1438R044 
 frameshift_variant 
 c.4857dup 
 p.His1620ThrfsTer42 
 De novo 
  
 Simplex 
 GEN1438R045 
 missense_variant 
 c.2532C>A 
 p.His844Gln 
 De novo 
  
 Simplex 
 GEN1438R046 
 inframe_deletion 
 c.1415_1423del 
 p.Ala472_Glu474del 
 De novo 
  
 Simplex 
 GEN1438R047 
 missense_variant 
 c.3808C>T 
 p.His1270Tyr 
 De novo 
  
 Simplex 
 GEN1438R048 
 missense_variant 
 c.2968C>T 
 p.Arg990Cys 
 De novo 
  
 Multiplex 
 GEN1438R049 
 missense_variant 
 c.3707A>G 
 p.Asn1236Ser 
 De novo 
  
 Simplex 
 GEN1438R050 
 synonymous_variant 
 c.6012C>T 
 p.His2004= 
 De novo 
  
 Multiplex 
 GEN1438R051 
 synonymous_variant 
 c.2685C>T 
 p.Pro895= 
 De novo 
  
 Multiplex 
 GEN1438R052 
 synonymous_variant 
 c.10797C>T 
 p.Pro3599= 
 De novo 
  
 Simplex 
 GEN1438R053 
 missense_variant 
 c.3707A>G 
 p.Asn1236Ser 
 De novo 
  
  
 GEN1438R054 
 missense_variant 
 c.4006G>A 
 p.Ala1336Thr 
 De novo 
  
  
 GEN1438R055 
 synonymous_variant 
 c.5805C>T 
 p.Arg1935= 
 De novo 
  
 Simplex 
 GEN1438R056 
 synonymous_variant 
 c.5256T>C 
 p.Val1752= 
 De novo 
  
 Multiplex 
 GEN1438R057 
 inframe_deletion 
 c.10533_10559del 
 p.Ser3513_Gly3521del 
 De novo 
  
  
 GEN1438R058 
 inframe_insertion 
 c.2333_2334insGGCGGC 
 p.Ala783_Ala784dup 
 De novo 
  
  
 GEN1438R059 
 missense_variant 
 c.2282G>C 
 p.Gly761Ala 
 De novo 
  
  
 GEN1438R060 
 synonymous_variant 
 c.2091G>A 
 p.Pro697= 
 De novo 
  
  
 GEN1438R061 
 missense_variant 
 c.1504G>A 
 p.Glu502Lys 
 De novo 
  
  
 GEN1438R062 
 missense_variant 
 c.1309G>C 
 p.Gly437Arg 
 De novo 
  
  
 GEN1438R063 
 synonymous_variant 
 c.900C>T 
 p.His300= 
 De novo 
  
  
 GEN1438R064 
 missense_variant 
 c.679G>A 
 p.Val227Ile 
 De novo 
  
  
 GEN1438R065 
 missense_variant 
 c.197C>T 
 p.Ala66Val 
 De novo 
  
  
 GEN1438R066 
 synonymous_variant 
 c.10533T>C 
 p.Gly3511= 
 De novo 
  
 Simplex 
 GEN1438R067 
 synonymous_variant 
 c.1416G>A 
 p.Ala472= 
 De novo 
  
  
 GEN1438R068 
 missense_variant 
 c.2578G>A 
 p.Glu860Lys 
 De novo 
  
  
 GEN1438R069 
 missense_variant 
 c.3731C>T 
 p.Thr1244Met 
 De novo 
  
  
 GEN1438R070 
 stop_gained 
 c.7056C>A 
 p.Tyr2352Ter 
 Familial 
  
 Simplex 
 GEN1438R071 
 missense_variant 
 c.212C>G 
 p.Pro71Arg 
 Unknown 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Duplication
 1
 
16
Duplication
 1
 
16
Duplication
 4
 
16
Deletion
 1
 
16
Duplication
 2
 
16
Deletion
 2
 
16
Duplication
 1
 
16
Deletion-Duplication
 9
 
16
Duplication
 4
 
16
Deletion
 1
 

No Animal Model Data Available

 

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