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Relevance to Autism

Shepherdson et al., 2024 described a cohort of 18 individuals with germline variants in the ZFX gene who presented with an X-linked neurodevelopmental disorder characterized by developmental delay/intellectual disability, behavioral abnormalities (including a diagnosis of autism spectrum disorder in six individuals), hypotonia, congenital anomalies, and recurrent facial features including thickening and medial broadening of the eyebrows, variations in facial shape, external eye abnormalities, long and/or smooth philtrum, and ear abnormalities. Additional functional assessment in Shepherdson et al., 2024 demonstrated that disease-associated ZFX missense variants resulted in altered target gene expression, while behavioral characterization of zfx knockout zebrafish demonstrated neurocognitive abnormalities. Additional coding variants in the ZFX gene have been previously identified in ASD probands (Chahrour et al., 2012; Ruzzo et al., 2019; Zhou et al., 2022).

Molecular Function

This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
DD, ID
ASD or autistic features, ADHD
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1436R001 
 missense_variant 
 c.2290C>T 
 p.Arg764Trp 
 Familial 
 Maternal 
 Simplex 
  et al.  
 GEN1436R002 
 missense_variant 
 c.2290C>T 
 p.Arg764Trp 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R003 
 missense_variant 
 c.2312C>T 
 p.Thr771Met 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R004 
 missense_variant 
 c.2312C>T 
 p.Thr771Met 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R005 
 missense_variant 
 c.2312C>T 
 p.Thr771Met 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R006 
 missense_variant 
 c.2321A>G 
 p.Tyr774Cys 
 Familial 
 Maternal 
 Extended multiplex 
  et al.  
 GEN1436R007 
 missense_variant 
 c.2321A>G 
 p.Tyr774Cys 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R008 
 missense_variant 
 c.2357G>A 
 p.Arg786Gln 
 Familial 
 Maternal 
  
  et al.  
 GEN1436R009 
 missense_variant 
 c.2357G>A 
 p.Arg786Gln 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R010 
 stop_gained 
 c.768dup 
 p.Lys257Ter 
 Familial 
 Maternal 
 Simplex 
  et al.  
 GEN1436R011 
 frameshift_variant 
 c.1319dup 
 p.Leu440PhefsTer21 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R012 
 frameshift_variant 
 c.1205_1206dup 
 p.Arg403GlufsTer12 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R013 
 frameshift_variant 
 c.1996_1997del 
 p.Met666ValfsTer2 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R014 
 frameshift_variant 
 c.529dup 
 p.Ser177PhefsTer12 
 De novo 
  
 Simplex 
  et al.  
 GEN1436R015 
 stop_gained 
 c.423_424del 
 p.Ser142Ter 
 Familial 
 Maternal 
 Simplex 
  et al.  
 GEN1436R016 
 frameshift_variant 
 c.115_116del 
 p.Val39PhefsTer14 
 Familial 
 Maternal 
 Simplex 
  et al.  
 GEN1436R017 
 missense_variant 
 G>C 
 p.Glu83Gln 
 Unknown 
  
 Multiplex (monozygotic twins) 
 GEN1436R018 
 splice_site_variant 
 c.-29+2924A>G 
  
 Familial 
 Maternal 
 Multiplex 
 GEN1436R019 
 synonymous_variant 
 c.1863G>A 
 p.Gln621= 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 18
 
X
Deletion
 1
 
X
Deletion
 2
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Duplication
 2
 
X
Deletion
 1
 
X
Deletion-Duplication
 21
 

No Animal Model Data Available

 

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