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

SFARI Gene Score

High Confidence, Syndromic Criteria 1.1, Syndromic

Autism Reports / Total Reports

15 / 39

Rare Variants / Common Variants

44 / 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.

SFARI Genomic Platforms

GPF browser SFARI genome browser

Reports (39)
Variants (45)
Gene Score
Associated CNVs (1)
Protein Interactions (4)

Reports related to NF1 (39 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	-	et al. ()	No	-
39	Support	-	et al. ()	No	-

Rare Variants (44)

Allele Change	Residue Change	Variant Type	Inheritance Pattern	Parental Transmission	Family Type	PubMed ID	Author, Year
-	-	microsatellite	-	-	-	11449390	Plank SM , et al. (2001)
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.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.4772+2T>C	-	splice_site_variant	De novo	-	Simplex	35982159	Zhou X et al. (2022)
c.3113+1G>A	-	splice_site_variant	Familial	Paternal	Multiplex	37799141	et al. ()
c.7470C>T	p.Val2490%3D	synonymous_variant	De novo	-	-	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.4267A>G	p.Lys1423Glu	missense_variant	Unknown	-	-	35253369	Verberne EA et al. (2022)
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.888+2T>G	-	splice_site_variant	De novo	-	Simplex	34580403	Pode-Shakked B et al. (2021)
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.5327C>A	p.Ser1776Ter	stop_gained	De novo	-	Simplex	27848944	Trujillano D , et al. (2016)
c.4143C>T	p.Ile1381%3D	synonymous_variant	De novo	-	Multiplex	35982159	Zhou X et al. (2022)
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.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.7910G>A	p.Arg2637Gln	missense_variant	Familial	Paternal	Multiplex	23999528	Toma C , et al. (2013)
c.6938del	p.Gly2313ValfsTer12	splice_site_variant	Familial	Maternal	-	36309498	Chan AJS et al. (2022)
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)

Current Score
Scoring History
3rd Party Scoring

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

See SFARI Gene'scoring criteria

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.

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

Score remained at 1

Description

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

Increased from S to 1

New Scoring Scheme

Description

Reports Added

[New Scoring Scheme]

1/1/2019

Increased from S to S

Description

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

Increased from S to S

Description

Reports Added

[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]

10/1/2016

Increased from S to S

Description

Reports Added

[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]

1/1/2016

Increased from S to S

Description

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

Increased from S to S

Description

Reports Added

[Large-scale discovery of novel genetic causes of developmental disorders.2014]

10/1/2014

Increased from S to S

Description

Reports Added

[Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1.2014]

4/1/2014

No data

Increased from No data to S

Description

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


17q11.2	Total Reports 27	CNV Type Deletion-Duplication	Case Populations / Individuals 42 / 113

External PIN Data

BioGRID Human Protein Reference Database

Interactome

Protein Binding
DNA Binding
RNA Binding
Protein Modification
Direct Regulation
ASD-Linked Genes

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

Human Gene Module / Chromosome 17 / NF1

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

SFARI Gene Score

Autism Reports / Total Reports

Rare Variants / Common Variants

EAGLE Score

Aliases

Associated Syndromes

Chromosome Band

Associated Disorders

Genetic Category

Relevance to Autism

Molecular Function

External Links

Human

Mouse

Fruit fly

SFARI Genomic Platforms

Reports related to NF1 (39 Reports)

Rare Variants (44)

Common Variants (1)

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

High Confidence

Syndromic

7/1/2020

Score remained at 1

Description

Reports Added

10/1/2019

Increased from S to 1

New Scoring Scheme

Description

Reports Added

1/1/2019

Increased from S to S

Description

Reports Added

10/1/2017

Increased from S to S

Description

Reports Added

10/1/2016

Increased from S to S

Description

Reports Added

1/1/2016

Increased from S to S

Description

Reports Added

1/1/2015

Increased from S to S

Description

Reports Added

10/1/2014

Increased from S to S

Description

Reports Added

4/1/2014

Increased from No data to S

Description

Reports Added

Krishnan Probability Score

Score 0.60552752749814

Ranking 333/25841 scored genes

ExAC Score

Score 0.99999984557026

Ranking 210/18225 scored genes

Sanders TADA Score

Score 0.72227551621555

Ranking 1312/18665 scored genes

Zhang D Score

Score -0.23470687392553

Ranking 16106/20870 scored genes

CNVs associated with NF1(1 CNVs)

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External PIN Data

Interactome