Human Gene Module / Chromosome 17 / NF1

NF1neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
8 / 25
Rare Variants / Common Variants
12 / 1
Aliases
NF1, Neurofibromin,  WSS,  NFNS,  VRNF,  DKFZp686J1293
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
17q11.2
Associated Disorders
DD/NDD, EPS, ID, ASD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. As well, genetic association has been found between the NF1 gene and autism. In particular, positive association was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004). However, other studies found no association with autism in French and South Carolina Autism Project cohorts. Separately, a rare mutation in NF1 has been identified in an individual with ASD (Sanders et al., 2012).

Molecular Function

The encoded protein has Ras GTPase activity and appears to be a negative regulator of cell proliferation.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
Reports related to NF1 (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Negative Association Association study of the NF1 gene and autistic disorder Mbarek O , et al. (1999) Yes -
2 Negative Association Lack of association of the (AAAT)6 allele of the GXAlu tetranucleotide repeat in intron 27b of the NF1 gene with autism Plank SM , et al. (2001) Yes -
3 Highly Cited Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1 Costa RM , et al. (2002) No -
4 Primary Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population Marui T , et al. (2004) Yes -
5 Recent Recommendation Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells Li F , et al. (2006) No -
6 Recent Recommendation Neurofibromin regulation of ERK signaling modulates GABA release and learning Cui Y , et al. (2008) No -
7 Recent Recommendation Aberrant expression of synaptic plasticity-related genes in the NF1+/- mouse hippocampus Park CS , et al. (2009) No -
8 Recent Recommendation Behavioural and cognitive phenotypes in children with neurofibromatosis type 1 (NF1): the link with the neurobiological level Hachon C , et al. (2010) No -
9 Highly Cited The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins Ballester R , et al. (1990) No -
10 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
11 Recent Recommendation ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities Wang Y , et al. (2012) No -
12 Recent Recommendation Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study Garg S , et al. (2012) No -
13 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
14 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
15 Recent Recommendation Autism traits in the RASopathies Adviento B , et al. (2013) No Autistic features
16 Recent Recommendation Neurofibromatosis type 1 and autism spectrum disorder Garg S , et al. (2013) No -
17 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
18 Recent Recommendation Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1 Plasschaert E , et al. (2014) No -
19 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
20 Recent Recommendation Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunction, and autistic mannerisms Huijbregts SC , et al. (2015) No -
21 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No ASD
22 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
23 Support Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2 Akamine S , et al. (2018) No DD, epilepsy/seizures
24 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
25 Support A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report Santoro C et al. (2020) No ASD, ID, epilepsy/seizures
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - microsatellite - - - 11449390 Plank SM , et al. (2001)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
c.4772+1G>T - splice_site_variant De novo NA - 29588991 Akamine S , et al. (2018)
c.3449C>G p.Ser1150Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.6792C>G p.Tyr2264Ter stop_gained De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5327C>A p.Ser1776Ter stop_gained De novo NA Simplex 27848944 Trujillano D , et al. (2016)
c.107C>G p.Thr36Ser missense_variant Familial Maternal - 27848944 Trujillano D , et al. (2016)
c.7375C>A p.His2459Asn missense_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.6579+2T>C - splice_site_variant De novo NA Extended multiplex 32873259 Santoro C et al. (2020)
c.1742dup p.Cys582LeufsTer6 frameshift_variant Familial Maternal - 30763456 Zhou WZ , et al. (2019)
c.7910G>A p.Arg2637Gln missense_variant Familial Paternal Multiplex 23999528 Toma C , et al. (2013)
c.5425C>T p.Pro1809Ser missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
N/A N/A microsatellite, intron_variant - - - 15389774 Marui T , et al. (2004)
SFARI Gene score
1S

High Confidence, Syndromic

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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."

7/1/2020
S
icon
S

Score remained at S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[New Scoring Scheme]
1/1/2019
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
7/1/2018
4S
icon
S

Decreased from 4S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

4/1/2018
S
icon
4S

Increased from S to 4S

Description

S

Reports Added
[Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.2018]
10/1/2017
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
10/1/2016
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Association study of the NF1 gene and autistic disorder.1999] [Lack of association of the (AAAT)6 allele of the GXAlu tetranucleotide repeat in intron 27b of the NF1 gene with autism.2001] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population.2004] [Autism traits in the RASopathies.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.1990] [Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.2002] [Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells.2006] [Neurofibromin regulation of ERK signaling modulates GABA release and learning.2008] [Aberrant expression of synaptic plasticity-related genes in the NF1 mouse hippocampus.2009] [Behavioural and cognitive phenotypes in children with neurofibromatosis type 1 (NF1): the link with the neurobiological level.2010] [ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.2012] [Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study.2012] [Neurofibromatosis type 1 and autism spectrum disorder.2013] [Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1.2014] [Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunc...2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]
1/1/2015
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
S
icon
S

Increased from S to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1.2014]
4/1/2014
No data
icon
S

Increased from No data to S

Description

Neurofibromatosis is a Mendelian disease associated with autism. There is some association and linkage evidence implicating it in idiopathic autism, including positive association that was found with a NF1 polymorphism in the Japanese population (Marui et al., 2004).

Reports Added
[Autism traits in the RASopathies.2013]
Krishnan Probability Score

Score 0.60552752749814

Ranking 333/25841 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 0.99999984557026

Ranking 210/18225 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 0.72227551621555

Ranking 1312/18665 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 -0.23470687392553

Ranking 16106/20870 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
CNVs associated with NF1(1 CNVs)
Sort By:
17q11.2 24 Deletion-Duplication 38  /  103
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
miR16 microRNA mir-16 Rat RNA Binding 100313997 N/A
TBPL1 TBP-like 1 Human DNA Binding 9519 P62380
TNFSF13B Tumor necrosis factor ligand superfamily member 13B Human Protein Binding 10673 Q9Y275
VSIG1 V-set and immunoglobulin domain-containing protein 1 Human Protein Binding 340547 Q86XK7
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