Human Gene Module / Chromosome 15 / FBN1

FBN1Fibrillin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 17
Rare Variants / Common Variants
27 / 0
Aliases
FBN1, ACMICD,  ECTOL1,  FBN,  GPHYSD2,  MASS,  MFS1,  OCTD,  SGS,  SSKS,  WMS,  WMS2
Associated Syndromes
-
Chromosome Band
15q21.1
Associated Disorders
DD/NDD
Relevance to Autism

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Molecular Function

This gene encodes a member of the fibrillin family. The encoded protein is a large, extracellular matrix glycoprotein that serve as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body. Mutations in this gene are associated with Marfan syndrome, isolated ectopia lentis, autosomal dominant Weill-Marchesani syndrome, MASS syndrome, and Shprintzen-Goldberg craniosynostosis syndrome.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FBN1 (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) No -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Recent Recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Homsy J , et al. (2016) No DD, learning disabilities
7 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No Heart malformation
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
9 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
10 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
11 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
12 Support - Woodbury-Smith M et al. (2022) Yes -
13 Support - Zhou X et al. (2022) Yes -
14 Support - Yuan B et al. (2023) Yes -
15 Support - Erica Rosina et al. (2024) No -
16 Support - Shenglan Li et al. (2024) No -
17 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1147+2T>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.494G>A p.Arg165Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1388G>A p.Gly463Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2384G>A p.Gly795Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2935G>A p.Ala979Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4313G>A p.Ser1438Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5543A>G p.Asn1848Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8039G>A p.Arg2680His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5396A>G p.Tyr1799Cys missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.3508C>T p.Arg1170Cys missense_variant De novo - - 26785492 Homsy J , et al. (2016)
c.248-151A>G - intron_variant Familial Paternal - 38593811 Shenglan Li et al. (2024)
c.2170A>G p.Ile724Val missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.621del p.Leu208SerfsTer122 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5274C>T p.Asp1758= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.3454G>A p.Ala1152Thr missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.4906G>A p.Gly1636Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5772C>A p.His1924Gln missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.1400C>T p.Pro467Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7338C>T p.Asn2446= synonymous_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.7708G>A p.Glu2570Lys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3971A>G p.Asn1324Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3216C>T p.Asp1072= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.284C>T p.Ser95Leu missense_variant Familial Maternal - 28333917 Vissers LE , et al. (2017)
c.4057G>A p.Gly1353Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.6917G>A p.Arg2306His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2323C>T p.Leu775Phe missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.5183C>T p.Ala1728Val missense_variant Familial Maternal Simplex 38041506 Erica Rosina et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis 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.

1/1/2020
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016]
7/1/2015
icon
3

Increased from to 3

Description

Two de novo missense variants in the FBN1 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2012 and Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. A third de novo missense variant in this gene was identified in De Rubeis et al., 2014

Krishnan Probability Score

Score 0.49039706011847

Ranking 6138/25841 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

Ranking 14/18225 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
Iossifov Probability Score

Score 0.986

Ranking 33/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.60074128330779

Ranking 711/18665 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 -0.077904784426238

Ranking 11493/20870 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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