Human Gene Module / Chromosome 8 / FGFR1

FGFR1fibroblast growth factor receptor 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
4 / 1
Aliases
FGFR1, BFGFR,  CD331,  CEK,  ECCL,  FGFBR,  FGFR-1,  FLG,  FLT-2,  FLT2,  HBGFR,  HH2,  HRTFDS,  KAL2,  N-SAM,  OGD,  bFGF-R-1
Associated Syndromes
-
Chromosome Band
8p11.23
Associated Disorders
-
Relevance to Autism

An intronic polymorphism in the FGFR1 gene (rs60527016) was the index SNP for a loci that reached genome-wide significance with ASD (odds ratio 0.84 (95% CI 0.790.90), P-value 4.70E-08) in a genome-wide association study on 6222 case-pseudocontrol pairs from the SPARK cohort (Matoba et al., 2020). Several rare de novo variants in the FGFR1 gene have been identified in ASD probands, including a splice-site variant (c.1971+5G>A) that was experimentally shown to result in retention of intron 14 of the FGFR1 gene and two de novo missense variants that were predicted to be damaging with REVEL scores > 0.5 (Satterstrom et al., 2020; Zhou et al., 2022; Li et al., 2023).

Molecular Function

The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FGFR1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Primary Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism Matoba N et al. (2020) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Recent Recommendation - Kuokuo Li et al. (2024) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.909C>G p.Asp303Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1971+5G>A - splice_site_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.761G>A p.Arg254Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2085C>T p.Gly695= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.92-12158A>G;c.-1-1733A>G;c.92-13671A>G;c.191-12158A>G - intron_variant - - - 32747698 Matoba N et al. (2020)
SFARI Gene score
2

Strong Candidate

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
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49663027429429

Ranking 2550/25841 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 0.98874428461417

Ranking 1854/18225 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 0.9467618546521

Ranking 17001/18665 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
Zhang D Score

Score -0.73165245594793

Ranking 20460/20870 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
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