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Relevance to Autism

Diagnostic exome sequencing in 100 patients with severe intellectual disability (ID) and their parents in de Ligt et al., 2012 identified a maternally-inherited missense variant in the TRPC5 gene in a male ID proband who was also diagnosed with autism spectrum disorder (ASD) and Tourette syndrome. Analysis of 54 male patients presenting with intellectual disability (ID) and a family history suggesting X-linked inheritance or maternal skewed X-chromosome inactivation using an X-chromosome-specific microarray in Mignon-Ravix et al., 2014 identified a deletion of the first exon of the TRPC5 gene in a child presenting with ID and autism spectrum disorder (ASD). Leitao et al., 2022 presented four previously unreported individuals with TRPC5 variants: three brothers with ASD and intellectual disability with a maternally-inherited missense variant that was experimentally confirmed to result in a constitutively active current; and a male patient with high-functioning ASD with a maternally-inherited nonsense variant. De novo coding variants in TRPC5 have also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), in patients with DD/ID (Deciphering Developmental Disorders Study 2015; Lelieveld et al., 2016), and in a proband with congenital heart disease (Homsy et al., 2015).

Molecular Function

This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Diagnostic exome sequencing in persons with severe intellectual disability.
ASD, TS, DD, ID
Support
Prevalence and architecture of de novo mutations in developmental disorders
Developmental disorders
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Support
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
Congenital heart disease
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes
ASD, DD, ID
Recent Recommendation
ASD, ID
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1366R001 
 missense_variant 
 c.1999C>A 
 p.Pro667Thr 
 Familial 
 Maternal 
 Simplex 
 GEN1366R002 
 copy_number_loss 
  
  
 Familial 
 Maternal 
  
 GEN1366R003 
 synonymous_variant 
 c.540G>A 
 p.Glu180%3D 
 De novo 
  
 Simplex 
 GEN1366R004 
 missense_variant 
 c.571C>T 
 p.Arg191Cys 
 De novo 
  
  
 GEN1366R005 
 missense_variant 
 c.1114G>T 
 p.Ala372Ser 
 De novo 
  
 Simplex 
 GEN1366R006 
 missense_variant 
 c.212G>A 
 p.Arg71Gln 
 De novo 
  
  
 GEN1366R007 
 missense_variant 
 c.523C>T 
 p.Arg175Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN1366R008 
 stop_gained 
 c.965G>A 
 p.Trp322Ter 
 Familial 
 Maternal 
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 21
 
X
Deletion
 2
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

No Animal Model Data Available

 

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