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Relevance to Autism

Two de novo loss-of-function (LoF) variants were identified in ASD probands in Yuen et al., 2017 (one in a proband from a simplex family, the other in a proband from a multiplex family). Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), KDM6A was determined to be an ASD candidate gene in Yuen et al., 2017.

Molecular Function

This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Mutations in the KDM6A gene are associated with Kabuki syndrome 2 (KABUK2; OMIM 300867), a congenital intellectual disability syndrome with additional features including postnatal dwarfism and distinct facial dysmorphic features.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
Support
A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.
Psychomotor retardation
Support
A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.
Kabuki syndrome 2
Support
KDM6A point mutations cause Kabuki syndrome.
Kabuki syndrome 2
Support
Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.
Kabuki syndrome 2
Support
Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population
ID
Support
Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN896R001 
 frameshift_variant 
 c.3217dup 
 p.Trp1073LeufsTer4 
 De novo 
 NA 
 Simplex 
 GEN896R002 
 splice_site_variant 
 G>A 
 p.? 
 De novo 
 NA 
 Multiplex 
 GEN896R003 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN896R004 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN896R005 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN896R006 
 splice_site_variant 
 c.975-1G>A 
  
 De novo 
 NA 
  
 GEN896R007 
 splice_site_variant 
 c.2988+1G>C 
  
 De novo 
 NA 
  
 GEN896R008 
 stop_gained 
 c.2944G>T 
 p.Gly982Ter 
 De novo 
 NA 
 Simplex 
 GEN896R009 
 stop_gained 
 c.1192C>T 
 p.Gln398Ter 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 15
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

Model Summary

Knockdown of kdm6a results in smaller craniofacial anatomy, which is rescued by wild-type kdm6a mRNA.

References

Type
Title
Author, Year
Primary
Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate.

Z_KDM6A_1_KD

Model Type: Genetic
Model Genotype: Wildtype
Mutation: Knockdown was performed by injecting a 2ng dose (1nl) of translation-blocking kdm6a morpholino into one-cell stage embryos.
Allele Type: Knockdown
Strain of Origin: Unreported
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source: Unreported

Z_KDM6A_2_KD_KDM6AL_KD

Model Type: Genetic
Model Genotype: Wildtype
Mutation: Double morpholino knockdown was performed by injecting a 1ng dose (1nl) of translation-blocking kdm6a morpholino and 1ng dose (1nl) of translation-blocking kdm6a-like morpholino into one-cell stage embryos.
Allele Type: Knockdown
Strain of Origin: Unreported
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source: Unreported

Z_KDM6A_1_KD

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Skeletal development: craniofacial1
Decreased
Description: Kdm6a morphants showed a decrease in the size of the lower jaw, hypoplastic Meckels cartilage, palatoquadrates, ceratohyals, and ceratobranchials compared to controls. Moreover, the in kdm6a morphants, the ethmoid plate failed to extend along its axis.
 Alcian blue staining
 96 hpf
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

Z_KDM6A_2_KD_KDM6AL_KD

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality1
Increased
Description: Double morphants showed an increase in early lethality compared to controls.
 General observations
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, 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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