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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.