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Table 1 Canonical Wnt pathway genes mutated in autism – summary of the evidence

From: A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

Gene

Gene location

Discovery strategy

Replications

Preclinical support

APC

5q21-q22

association study 75 unrelated patients

single case of APC deletion

APC’s functional role

DISC1

1q42

association study in 144 families

no

DISC1 function

EN2

7q36

association study in 3 datasets of 518 families

yes, but opposite haplotype

Wnt target gene

MET

7q31

association studies in 4 cohorts; microdeletion in 2 pts (involving >25 genes)

yes

post mortem expression; animal data

WIF1

12q14.3

GWAS in 26 extended families; linkage peak of ≥19 genes

no

 

MARK1

14q41

GWAS in 116 families; SNPs in MARK1

no

transcription of MARK1 altered by SNPs

CDH10

5p14.1

GWAS in 780 families; SNPs between CDH9 and CDH10 highly significant

replication cohort by the same authors

 

WNT2

7q31.2

GWAS study in 75 families; 2 families with missense mutation in Wnt2

one positive, also two negative studies

role of Wnt2 in midbrain development

PTPRZ1

7q31.3

single case with deletion CNV of 20 genes

no

 

CDH15

16q24.3

genome scanning; deletion CNV of 3 genes

no

 

CDH13

16q23.3

GWAS; deletion CNV of single gene

no

 

CDH8

16q21

GWAS; detection of rare deletion CNV

no

data from KO mice

DOCK4

7q31.1

GWAS; microdeletion CNV

no, but dyslexia cases

biochemical data

BCL9

1q21

deletion and duplication CNVs (14 genes)

multiple

 

FZD9

7q11.23

recognized syndrome; deletion and duplication CNVs (>20 genes)

yes, multiple

Wnt2 receptor

AHI1

6q23.3

recognized syndrome: mutation screening identified multiple disruptive mutations

yes, multiple

 

CREBBP

16p13.3

recognized syndrome; microdeletion CNVs and disruptive mutations

multiple, also cases with microduplications

data from KO mice

TSC1/2

9q34 / 16p13.3

recognized syndrome: mutation screening identified numerous missense mutations

yes, multiple

data from KO mice

  1. The genes have been ranked according to their discovery process. Association studies of candidate gene studies have frequently yielded false positive results and are considered relatively weak evidence. Genome wide association studies followed by specific investigation of genes in the ‘hot spot’ may be more reliable, but replications are crucial. Copy number variations may provide good evidence but the duplicated or deleted regions are generally large and usually contain several candidate genes. Copy number variations that involve only a few or even a single gene give a strong indication for a pathological role of those genes, but thus far such CNVs have been detected only very rarely and lack replication. The best evidence comes from CNVs that give rise to recognizable syndromes. Unfortunately, in this case the involved genes are not specific for the canonical Wnt pathway and modify other pathways as well. In some cases, there is circumstantial support for a given gene from biochemical- or whole animal studies. Abbreviations: CNV, copy number variation; GWAS, genome wide association study; SNP, single nucleotide polymorphism. For details, please refer to the individual section in the text.
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Molecular Autism

ISSN: 2040-2392