Human Gene Module / Chromosome 17 / NF1

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

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
19 / 45
Rare Variants / Common Variants
54 / 1
EAGLE Score
9.3
Moderate Learn More
Aliases
NF1, Neurofibromin,  WSS,  NFNS,  VRNF,  DKFZp686J1293
Associated Syndromes
-
Chromosome Band
17q11.2
Associated Disorders
DD/NDD, ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

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). Chisholm et al., 2022 analyzed a study cohort of 68 children (3-15 years) with neurofibromatosis type I (NF1) who had scored above threshold on the Social Responsiveness Scale-Second Edition (T-score 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and found that 63% met the ADOS-2 'autism spectrum' cut-off, while 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Large-scale whole-exome and whole-genome seqeuncing studies have identified de novo variants in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (Sanders et al., 2012; Iossifov et al., 2014; Zhou et al., 2022). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified NF1 as a gene reaching exome-wide significance (P < 2.5E-06).

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
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Mouse
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Entrez Gene
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Reports related to NF1 (45 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
26 Support - Pode-Shakked B et al. (2021) Yes -
27 Support - Cummings K et al. (2022) No ASD
28 Support - Verberne EA et al. (2022) No -
29 Support - Chuan Z et al. (2022) No -
30 Support - Hu C et al. (2022) Yes -
31 Recent Recommendation - Zhou X et al. (2022) Yes -
32 Support - Chan AJS et al. (2022) Yes Neurofibromatosis type I
33 Support - Dyson A et al. (2022) No -
34 Support - Zhang Y et al. (2023) Yes ID, learning disability
35 Support - Santos S et al. (2023) Yes -
36 Support - Sheth F et al. (2023) Yes DD, ID
37 Support - Durkin J et al. (2023) No -
38 Support - Amerh S Alqahtani et al. (2023) No -
39 Support - Leonard D Kuhrt et al. (2023) No -
40 Support - Ruohao Wu et al. (2024) No -
41 Support - Axel Schmidt et al. (2024) Yes -
42 Support - Suhua Chang et al. () Yes -
43 Support - Karen Lob et al. () Yes ADHD, DD, ID, epilepsy/seizures
44 Support - Soo-Whee Kim et al. (2024) Yes -
45 Support - Chengyan Li et al. (2024) No -
Rare Variants   (54)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - microsatellite - - - 11449390 Plank SM , et al. (2001)
c.910C>T p.Arg304Ter stop_gained De novo - - 39136901 Karen Lob et al. ()
c.6365-2A>G - splice_site_variant Unknown - - 39136901 Karen Lob et al. ()
c.3496+2T>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.7000-1G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.731-1G>T - splice_site_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1246C>T p.Arg416Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.6792C>A p.Tyr2264Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.6930T>A p.Pro2310%3D stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.7846C>T p.Gln2616Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1885G>A p.Gly629Arg missense_variant De novo - - 35741772 Hu C et al. (2022)
c.7395-2A>T p.? splice_site_variant De novo - - 37035742 Zhang Y et al. (2023)
c.4772+1G>T - splice_site_variant De novo - - 29588991 Akamine S , et al. (2018)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
c.3610C>G p.Arg1204Gly missense_variant De novo - - 39136901 Karen Lob et al. ()
c.2684T>G p.Met895Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4562T>G p.Leu1521Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5794C>G p.Leu1932Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7163C>T p.Thr2388Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8164C>G p.Leu2722Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7470C>T p.Val2490= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4772+2T>C - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2041C>T p.Arg681Ter stop_gained De novo - Simplex 37543562 Sheth F et al. (2023)
c.4207G>T p.Ala1403Ser splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.412G>C p.Ala138Pro missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.4267A>G p.Lys1423Glu missense_variant Unknown - - 35253369 Verberne EA et al. (2022)
c.2585C>G p.Thr862Ser missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.3449C>G p.Ser1150Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.6792C>G p.Tyr2264Ter stop_gained De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.3103A>G p.Met1035Val missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.888+2T>G - splice_site_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.6311T>C p.Leu2104Pro missense_variant Familial Maternal - 39136901 Karen Lob et al. ()
c.701del p.Leu234ArgfsTer47 frameshift_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.8188C>T p.Leu2730Phe missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.4143C>T p.Ile1381= synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5327C>A p.Ser1776Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.3089C>T p.Ser1030Leu missense_variant Familial Paternal - 36309498 Chan AJS et al. (2022)
c.7375C>A p.His2459Asn missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.107C>G p.Thr36Ser missense_variant Familial Maternal - 27848944 Trujillano D , et al. (2016)
c.3938_3941del p.Asp1313GlyfsTer13 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.7622_7623del p.Gly2541AspfsTer14 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.653_654delinsT p.Lys218MetfsTer7 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.276del p.Lys92AsnfsTer11 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.6579+2T>C - splice_site_variant De novo - Extended multiplex 32873259 Santoro C et al. (2020)
c.5754del p.Asn1918LysfsTer7 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1742dup p.Cys582LeufsTer6 frameshift_variant Familial Maternal - 30763456 Zhou WZ , et al. (2019)
c.2288T>C p.Leu763Pro missense_variant Familial Maternal Simplex 38764027 Ruohao Wu et al. (2024)
c.7910G>A p.Arg2637Gln missense_variant Familial Paternal Multiplex 23999528 Toma C , et al. (2013)
c.1511del p.Pro504GlnfsTer22 frameshift_variant De novo - Simplex 39528574 Chengyan Li et al. (2024)
c.6938del p.Gly2313ValfsTer12 splice_site_variant Familial Maternal - 36309498 Chan AJS et al. (2022)
c.3113+1G>A - splice_site_variant Familial Paternal Multiplex 37799141 Amerh S Alqahtani et al. (2023)
c.7996_7997del p.Asn2666HisfsTer26 frameshift_variant Familial Maternal - 36309498 Chan AJS et al. (2022)
c.499_502del p.Cys167GlnfsTer10 frameshift_variant Familial Paternal Simplex 36309498 Chan AJS et al. (2022)
c.5425C>T p.Pro1809Ser missense_variant De novo - 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

Score Delta: Score remained at 1S

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
1
icon
1

Score remained at 1

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]
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 30 Deletion-Duplication 45  /  121
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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