Human Gene Module / Chromosome 4 / FAT1

FAT1FAT atypical cadherin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
12 / 13
Rare Variants / Common Variants
25 / 0
Aliases
FAT1, CDHF7,  CDHR8,  FAT,  ME5,  hFat1
Associated Syndromes
-
Chromosome Band
4q35.2
Associated Disorders
-
Relevance to Autism

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Molecular Function

This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FAT1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders Kenny EM , et al. (2013) Yes -
3 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
6 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
7 Support - Frei JA et al. (2021) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Kim IB et al. (2022) Yes -
10 Support - Hernando-Davalillo C et al. (2022) Yes DD
11 Support - Zhou X et al. (2022) Yes -
12 Support - Tuncay IO et al. (2023) Yes -
13 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 35861186 Hernando-Davalillo C et al. (2022)
c.3784C>T p.Arg1262Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.3973-7G>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.12104-1G>A - splice_site_variant De novo - - 31452935 Feliciano P et al. (2019)
c.5312C>T p.Thr1771Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.10819A>G p.Ile3607Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.12634C>G p.His4212Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.13256C>T p.Ala4419Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.12104-1G>A - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.12909C>T p.Ser4303%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2473G>T p.Glu825Ter stop_gained Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.3649G>T p.Val1217Leu missense_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.8910A>C p.Glu2970Asp missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.9823C>A p.His3275Asn missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1568A>G p.Glu523Gly missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.11072A>G p.His3691Arg missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.4790T>A p.Val1597Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.8971A>T p.Asn2991Tyr missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.970G>T p.Asp324Tyr missense_variant Familial Paternal Simplex 35840799 Kim IB et al. (2022)
c.9163A>G p.Asn3055Asp missense_variant Familial Maternal Simplex 35840799 Kim IB et al. (2022)
c.8620G>T p.Glu2874Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2252_2253del p.Lys751ThrfsTer10 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3803G>A p.Arg1268Gln missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.4754C>T p.Thr1585Met missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.12653A>G p.Asp4218Gly missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Reports Added
[Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism2021]
7/1/2020
3
icon
3

Decreased from 3 to 3

Description

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

Rare de novo missense variants in the FAT1 gene have been identified in ASD probands by whole-exome sequencing in two reports (Neale et al., 2012; Iossifov et al., 2014), while inherited damaging missense variants in FAT1 have been observed in affected individuals from three extended multiplex ASD families (Cukier et al., 2014).

Krishnan Probability Score

Score 0.44488958900673

Ranking 15674/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 1.7790587837974E-10

Ranking 16860/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.95011340794851

Ranking 18363/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 11

Ranking 171/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.29694697164933

Ranking 2792/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACF2 Endo-1,3(4)-beta-glucanase 2 Baker's yeast Protein Binding 850836 Q12168
AYR1 NADPH-dependent 1-acyldihydroxyacetone phosphate reductase Baker's yeast Protein Binding 854682 P40471
C2ORF48 chromosome 2 open reading frame 48 Human Protein Binding 348738 Q96LS8
EHT1 Medium-chain fatty acid ethyl ester synthase/esterase 2 Baker's yeast Protein Binding 852476 P38295
ERG27 3-keto-steroid reductase Baker's yeast Protein Binding 850790 Q12452
ERG7 Lanosterol synthase Baker's yeast Protein Binding 856470 P38604
FAA1 Faa1p Baker's yeast Protein Binding 854495 P30624
FAM5C BMP/retinoic acid-inducible neural-specific protein 3 Human Protein Binding 339479 Q76B58
GCN1 GCN1 eIF2 alpha kinase activator homolog Human Protein Binding 10985 Q92616
GML Glycosyl-phosphatidylinositol-anchored molecule-like protein Human Protein Binding 2765 Q99445
GTT1 Glutathione S-transferase 1 Baker's yeast Protein Binding 854856 P40582
HACD3 3-hydroxyacyl-CoA dehydratase 3 Human Protein Binding 51495 Q9P035
IFNE Interferon epsilon Human Protein Binding 338376 Q86WN2
KES1 Protein KES1 Baker's yeast Protein Binding 855958 P35844
KLC3 kinesin light chain 3 Human Protein Binding 147700 Q6P597
LOA1 Loa1p Baker's yeast Protein Binding 856261 Q06508
NXPH2 Neurexophilin-2 Human Protein Binding 11249 O95156
PDGFB platelet-derived growth factor beta polypeptide Human Protein Binding 5155 P01127
PMP3 Plasma membrane proteolipid 3 Baker's yeast Protein Binding 851869 P87284
POMGNT2 protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4-) Human Protein Binding 84892 Q8NAT1
PSG8 Pregnancy-specific beta-1-glycoprotein 8 Human Protein Binding 440533 Q9UQ74
RER2 Dehydrodolichyl diphosphate synthase RER2 Baker's yeast Protein Binding 852287 P35196
SAS10 Something about silencing protein 10 Baker's yeast Protein Binding 851403 Q12136
SLAMF1 Signaling lymphocytic activation molecule Human Protein Binding 6504 Q13291
SLC1 N/A Baker's yeast Protein Binding 851508 N/A
SNA3 Protein SNA3 Baker's yeast Protein Binding 853290 P14359
TGL1 Sterol esterase TGL1 Baker's yeast Protein Binding 853717 P34163
UBI4 Polyubiquitin Baker's yeast Protein Binding 850620 P0CG63
Vasp vasodilator-stimulated phosphoprotein Rat Protein Binding 361517 B5DEX4
XPOT exportin, tRNA Human Protein Binding 11260 O43592
YEH1 Sterol esterase 1 Baker's yeast Protein Binding 850648 Q07804
YJU3 Monoglyceride lipase Baker's yeast Protein Binding 853768 P28321
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