Human Gene Module / Chromosome 9 / NFIB

NFIBnuclear factor I B

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
16 / 0
Aliases
NFIB, CTF,  HMGIC/NFIB,  NF-I/B,  NF1-B,  NFI-B,  NFI-RED2,  NFIB3, NFIB
Associated Syndromes
-
Chromosome Band
9p23-p22.3
Associated Disorders
ASD
Relevance to Autism

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with mild intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features. NFIB was found to bind to a transcriptional activator containing an ASD-associated intronic haplotype in the EN2 gene (Choi et al., 2012).

Molecular Function

Recognizes and binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3' present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NFIB (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function Choi J , et al. (2011) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly Schanze I , et al. (2018) No ASD or autistic features
4 Recent Recommendation Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes Hickey SL , et al. (2019) No -
5 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
6 Support - Gana S et al. (2023) Yes -
7 Support - Marketa Wayhelova et al. (2024) No -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 30388402 Schanze I , et al. (2018)
- - copy_number_loss Unknown - - 30388402 Schanze I , et al. (2018)
- - copy_number_loss De novo - - 31452935 Feliciano P et al. (2019)
- - copy_number_loss De novo - Simplex 30388402 Schanze I , et al. (2018)
- - copy_number_loss Familial - Multiplex 30388402 Schanze I , et al. (2018)
- - copy_number_loss Familial Maternal Simplex 30388402 Schanze I , et al. (2018)
c.341A>C p.Lys114Thr missense_variant Unknown - - 30388402 Schanze I , et al. (2018)
c.376A>G p.Lys126Glu missense_variant De novo - - 30388402 Schanze I , et al. (2018)
c.395T>C p.Leu132Pro missense_variant De novo - - 30388402 Schanze I , et al. (2018)
c.109C>T p.Arg37Ter stop_gained De novo - Simplex 30388402 Schanze I , et al. (2018)
c.265C>T p.Arg89Ter stop_gained Unknown - Simplex 30388402 Schanze I , et al. (2018)
c.806+1G>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.115C>T p.Arg39Cys missense_variant Familial Maternal Simplex 36756855 Gana S et al. (2023)
c.662C>G p.Ser221Ter stop_gained Familial Paternal - 38321498 Marketa Wayhelova et al. (2024)
c.1063_1076del p.Ile355SerfsTer48 frameshift_variant De novo - - 30388402 Schanze I , et al. (2018)
c.758_759insTG p.Met253IlefsTer26 frameshift_variant Familial Maternal Simplex 30388402 Schanze I , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features.

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features.

Reports Added
[Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.2019]
10/1/2018
icon
4S

Increased from to 4S

Description

A de novo loss-of-function variant in the NFIB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Schanze et al., 2018 reported 18 individuals haploinsufficent for the NFIB gene (10 individuals with microdeletions affecting NFIB, five individuals with truncating variants, and three individuals with missense variants that resulted in significantly reduced transcriptional activity) that presented with intellectual disability or learning disability, speech delay, and macrocephaly; behavioral abnormalities were frequently observed in this cohort, with five cases presenting with ASD or autistic features.

Krishnan Probability Score

Score 0.60892642166866

Ranking 271/25841 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 0.99080916701879

Ranking 1775/18225 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 0.827

Ranking 213/239 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 0.44986512348151

Ranking 352/18665 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 0.2794012931883

Ranking 3043/20870 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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