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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

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population.
ASD
Negative Association
Association study of the NF1 gene and autistic disorder.
ASD
Negative Association
Lack of association of the (AAAT)6 allele of the GXAlu tetranucleotide repeat in intron 27b of the NF1 gene with autism.
ASD
Support
ASD
ID, learning disability
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Palsy, motor neuron atrophy, muscle weakness
Support
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
ADHD, DD, ID
Support
A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies
ASD
Support
Loss of NF1 in Drosophila Larvae Causes Tactile Hypersensitivity and Impaired Synaptic Transmission at the Neuromuscular Junction
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Neurofibromin 1 mutations impair the function of human induced pluripotent stem cell-derived microglia
Neurofibromatosis type I
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
Neurofibromatosis type 1
ASD, ID, epilepsy/seizures
Support
Trio-whole exome sequencing reveals the importance of de novo variants in children with intellectual disability and developmental delay
DD, epilepsy/seizures
Support
Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
ASD
Neurofibromatosis type I
Support
Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.
ASD
Support
Prospect of genetic disorders in Saudi Arabia
DD
Support
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...
ASD
Support
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism
ASD
Support
Clinical Targeted Panel Sequencing Analysis in Clinical Evaluation of Children with Autism Spectrum Disorder in China
ASD
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.
Neurofibromatosis type 1
DD, epilepsy/seizures
Support
Genetic Diagnostic Yield in Autism Spectrum Disorder (ASD) and Epilepsy Phenotypes in Children with Genetically Defined ASD
ASD, Neurofibromatosis type I
ADHD, DD, ID, epilepsy/seizures
Support
Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy
Epilepsy/seizures
Support
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
ASD
Support
ASD
DD, ID
Support
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Epilepsy/seizures
DD/ID
Support
Whole-genome sequencing identifies novel genes for autism in Chinese trios
ASD
Support
Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean
DD
Support
Neurofibromatosis type I, ASD
Support
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Hypotonia
ASD
Support
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
ASD, ADHD
Support
Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics
Neurofibromatosis type I
ASD
Highly Cited
The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.
Highly Cited
Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.
Recent Recommendation
Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study.
Recent Recommendation
ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.
Recent Recommendation
Integrating de novo and inherited variants in 42
ASD
Recent Recommendation
Behavioural and cognitive phenotypes in children with neurofibromatosis type 1 (NF1): the link with the neurobiological level.
Recent Recommendation
Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunc...
Recent Recommendation
Aberrant expression of synaptic plasticity-related genes in the NF1 mouse hippocampus.
Recent Recommendation
Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1.
Recent Recommendation
Neurofibromin regulation of ERK signaling modulates GABA release and learning.
Recent Recommendation
Neurofibromatosis type 1 and autism spectrum disorder.
Recent Recommendation
Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells.
Recent Recommendation
Autism traits in the RASopathies.
Neurofibromatosis type 1
Autistic features
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN169R001 
 microsatellite 
  
  
  
  
  
 GEN169R002 
 missense_variant 
 c.7375C>A 
 p.His2459Asn 
 De novo 
  
 Simplex 
 GEN169R003 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Unknown 
 GEN169R004 
 missense_variant 
 c.7910G>A 
 p.Arg2637Gln 
 Familial 
 Paternal 
 Multiplex 
 GEN169R005 
 missense_variant 
 c.5425C>T 
 p.Pro1809Ser 
 De novo 
  
 Simplex 
 GEN169R006 
 stop_gained 
 c.3449C>G 
 p.Ser1150Ter 
 De novo 
  
 Simplex 
 GEN169R007 
 missense_variant 
 c.107C>G 
 p.Thr36Ser 
 Familial 
 Maternal 
  
 GEN169R008 
 stop_gained 
 c.5327C>A 
 p.Ser1776Ter 
 De novo 
  
 Simplex 
 GEN169R009 
 stop_gained 
 c.6792C>G 
 p.Tyr2264Ter 
 De novo 
  
 Simplex 
 GEN169R010 
 splice_site_variant 
 c.4772+1G>T 
  
 De novo 
  
  
 GEN169R011 
 frameshift_variant 
 c.1742dup 
 p.Cys582LeufsTer6 
 Familial 
 Maternal 
  
 GEN169R012 
 frameshift_variant 
 c.1742dup 
 p.Cys582LeufsTer6 
 Familial 
 Maternal 
  
 GEN169R013 
 frameshift_variant 
 c.1742dup 
 p.Cys582LeufsTer6 
 Familial 
 Maternal 
  
 GEN169R014 
 splice_site_variant 
 c.6579+2T>C 
  
 De novo 
  
 Extended multiplex 
 GEN169R015 
 splice_site_variant 
 c.888+2T>G 
  
 De novo 
  
 Simplex 
 GEN169R016 
 missense_variant 
 c.4267A>G 
 p.Lys1423Glu 
 Unknown 
  
  
 GEN169R017 
 missense_variant 
 c.1885G>A 
 p.Gly629Arg 
 De novo 
  
  
 GEN169R018 
 frameshift_variant 
 c.701del 
 p.Leu234ArgfsTer47 
 Unknown 
  
  
 GEN169R019 
 splice_site_variant 
 c.731-1G>T 
  
 Unknown 
  
  
 GEN169R020 
 missense_variant 
 c.5794C>G 
 p.Leu1932Val 
 De novo 
  
  
 GEN169R021 
 stop_gained 
 c.6930T>A 
 p.Pro2310%3D 
 De novo 
  
  
 GEN169R022 
 splice_site_variant 
 c.7000-1G>C 
  
 De novo 
  
  
 GEN169R023 
 synonymous_variant 
 c.4143C>T 
 p.Ile1381%3D 
 De novo 
  
 Multiplex 
 GEN169R024 
 splice_site_variant 
 c.4772+2T>C 
  
 De novo 
  
 Simplex 
 GEN169R025 
 frameshift_variant 
 c.5754del 
 p.Asn1918LysfsTer7 
 De novo 
  
 Simplex 
 GEN169R026 
 frameshift_variant 
 c.653_654delinsT 
 p.Lys218MetfsTer7 
 De novo 
  
  
 GEN169R027 
 missense_variant 
 c.2684T>G 
 p.Met895Arg 
 De novo 
  
  
 GEN169R028 
 frameshift_variant 
 c.3938_3941del 
 p.Asp1313GlyfsTer13 
 De novo 
  
  
 GEN169R029 
 stop_gained 
 c.6792C>A 
 p.Tyr2264Ter 
 De novo 
  
  
 GEN169R030 
 synonymous_variant 
 c.7470C>T 
 p.Val2490%3D 
 De novo 
  
  
 GEN169R031 
 frameshift_variant 
 c.7622_7623del 
 p.Gly2541AspfsTer14 
 De novo 
  
  
 GEN169R032 
 missense_variant 
 c.8164C>G 
 p.Leu2722Val 
 De novo 
  
  
 GEN169R033 
 stop_gained 
 c.1246C>T 
 p.Arg416Ter 
 De novo 
  
  
 GEN169R034 
 splice_site_variant 
 c.3496+2T>G 
  
 De novo 
  
  
 GEN169R035 
 splice_site_variant 
 c.4207G>T 
 p.Ala1403Ser 
 De novo 
  
  
 GEN169R036 
 missense_variant 
 c.4562T>G 
 p.Leu1521Arg 
 De novo 
  
  
 GEN169R037 
 missense_variant 
 c.7163C>T 
 p.Thr2388Ile 
 De novo 
  
  
 GEN169R038 
 stop_gained 
 c.7846C>T 
 p.Gln2616Ter 
 De novo 
  
  
 GEN169R039 
 missense_variant 
 c.3089C>T 
 p.Ser1030Leu 
 Familial 
 Paternal 
  
 GEN169R040 
 frameshift_variant 
 c.7996_7997del 
 p.Asn2666HisfsTer26 
 Familial 
 Maternal 
  
 GEN169R041 
 splice_site_variant 
 c.6938del 
 p.Gly2313ValfsTer12 
 Familial 
 Maternal 
  
 GEN169R042 
 frameshift_variant 
 c.499_502del 
 p.Cys167GlnfsTer10 
 Familial 
 Paternal 
 Simplex 
 GEN169R043 
 splice_site_variant 
 c.7395-2A>T 
 p.? 
 De novo 
  
  
 GEN169R044 
 stop_gained 
 c.2041C>T 
 p.Arg681Ter 
 De novo 
  
 Simplex 
 GEN169R045 
 missense_variant 
 c.8188C>T 
 p.Leu2730Phe 
 Unknown 
  
 Simplex 
 GEN169R046 
 splice_site_variant 
 c.3113+1G>A 
  
 Familial 
 Paternal 
 Multiplex 
 GEN169R047 
 missense_variant 
 c.2288T>C 
 p.Leu763Pro 
 Familial 
 Maternal 
 Simplex 
 GEN169R048 
 splice_site_variant 
 c.6365-2A>G 
  
 Unknown 
  
  
 GEN169R049 
 missense_variant 
 c.6311T>C 
 p.Leu2104Pro 
 Familial 
 Maternal 
  
 GEN169R050 
 missense_variant 
 c.3610C>G 
 p.Arg1204Gly 
 De novo 
  
  
 GEN169R051 
 stop_gained 
 c.910C>T 
 p.Arg304Ter 
 De novo 
  
  
 GEN169R052 
 frameshift_variant 
 c.276del 
 p.Lys92AsnfsTer11 
 De novo 
  
 Simplex 
 GEN169R053 
 missense_variant 
 c.2585C>G 
 p.Thr862Ser 
 Unknown 
  
  
 GEN169R054 
 missense_variant 
 c.412G>C 
 p.Ala138Pro 
 De novo 
  
  
 GEN169R055 
 missense_variant 
 c.3103A>G 
 p.Met1035Val 
 De novo 
  
  
 GEN169R056 
 frameshift_variant 
 c.1511del 
 p.Pro504GlnfsTer22 
 De novo 
  
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
17
Duplication
 2
 
17
Deletion-Duplication
 29
 
17
Deletion
 2
 
17
Deletion-Duplication
 78
 

Model Summary

New roles for NF1 in development and indicate that some of the abnormal growth phenomena observed in NF1 patients can be recapitulated in neurofibromin deficient mice.

References

Type
Title
Author, Year
Additional
Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1.
Additional
Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain.
Additional
Neurofibromin is required for barrel formation in the mouse somatosensory cortex.
Additional
Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.
Additional
Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.
Primary
Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted deletion of exon 23a from Nf1 gene.
Allele Type: Targeted (Knock-Out)
Strain of Origin: C57BL/6J
Genetic Background: Not Specified
ES Cell Line: CJ.7
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Spatial learning1
Abnormal
 Morris water maze test
 Unreported
Cued or contextual fear conditioning: context discrimination1
Abnormal
 NA
 Unreported
Developmental trajectory1
 No change
 General observations
 Unreported
Protein expression level evidence1
 No change
 Western blot
 Unreported
Regulation of gene expression1
 No change
 Quantitative pcr (qrt-pcr)
 Unreported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Brain morphology1
 No change
 Histology
 Unreported
Vision1
 No change
 Morris water maze test
 Unreported
Vision1
 No change
 Morris water maze test
 Unreported
Social transmission of food preference1
 No change
 NA
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Maternal behavior, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
Actg1 actin, gamma, cytoplasmic 1 11465 P63260 IP; LC-MS/MS
Omrani A , et al. 2015
APP amyloid beta (A4) precursor protein 351 P05067 Y2H; IP/WB
De Schepper S , et al. 2005
C19ORF75 SIGLEC family-like protein 1 284369 Q8N7X8 IP; LC-MS/MS
Huttlin EL , et al. 2015
CA14 Carbonic anhydrase 14 23632 Q9ULX7 IP; LC-MS/MS
Huttlin EL , et al. 2015
Cask calcium/calmodulin-dependent serine protein kinase (MAGUK family) 29647 Q62915 IP/WB
Hsueh YP , et al. 2001
CD79B B-cell antigen receptor complex-associated protein beta chain 974 P40259-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
Cul3 cullin 3 26554 Q9JLV5 IP/WB
Hollstein PE and Cichowski K 2013
Ddah1 dimethylarginine dimethylaminohydrolase 1 64157 O08557 GST; Reversed-phase chromatography (RPC)
Tokuo H , et al. 2001
DNAJC7 DnaJ (Hsp40) homolog, subfamily C, member 7 7266 Q99615 Y2H
Murthy AE , et al. 1996
Dpysl2 dihydropyrimidinase-like 2 12934 O08553 IP; LC-MS/MS
Omrani A , et al. 2015
EFS embryonal Fyn-associated substrate 10278 O43281 Y2H
Sakai Y , et al. 2011
EHMT1 G9a 30971 Q95RU8 ChIP-Seq
Kramer JM , et al. 2011
EPHA1 EPH receptor A1 2041 P21709 IP; LC-MS/MS
Huttlin EL , et al. 2015
FAM174A Membrane protein FAM174A 345757 Q8TBP5 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
Grin1 glutamate receptor, ionotropic, NMDA1 (zeta 1) 14810 P35438 Affinity chromatography; IP/WB
Husi H , et al. 2000
Grin2b glutamate receptor, ionotropic, NMDA2B (epsilon 2) 14812 Q01097 Peptide affinity chromatography
Husi H , et al. 2000
Hcn1 hyperpolarization-activated, cyclic nucleotide-gated K+ 1 15165 O88704 IP; LC-MS/MS; IP/WB
Omrani A , et al. 2015
HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog 3265 P01112 IP/WB
Hirata Y , et al. 2015
HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog 3265 P01112 Y2H; GTP hydrolysis assay
Morcos P , et al. 1996
Mbp myelin basic protein 17196 P04370 IP; LC-MS/MS
Omrani A , et al. 2015
MET met proto-oncogene 17295 P16056 IP; LC-MS/MS
Xie Z , et al. 2016
MIB1 mindbomb E3 ubiquitin protein ligase 1 307594 D3ZUV2 Affinity chromatography; LC-MS/MS
Mertz J , et al. 2015
miR16 microRNA mir-16 100313997 N/A Peptide microarray; in silico target prediction
Pan Q , et al. 2014
P4HA3 prolyl 4-hydroxylase, alpha polypeptide III 283208 Q7Z4N8 IP; LC-MS/MS
Huttlin EL , et al. 2015
Paics phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoribosylaminoimidazole, succinocarboxamide synthetase 67054 Q9DCL9 IP; LC-MS/MS
Omrani A , et al. 2015
SCN3B sodium channel, voltage-gated, type III, beta subunit 55800 Q9NY72 IP; LC-MS/MS
Huttlin EL , et al. 2015
SDC1 syndecan 1 6382 P18827 Y2H
Hsueh YP , et al. 2001
SDC2 syndecan 2 6383 P34741 Y2H; GST
Hsueh YP , et al. 2001
SDC3 syndecan 3 9672 O75056 Y2H; IP/WB
Hsueh YP , et al. 2001
SDC4 syndecan 4 6385 P31431 Y2H
Hsueh YP , et al. 2001
SPRED1 Sprouty-related, EVH1 domain-containing protein 1 161742 Q7Z699 IP/WB
Pasmant E , et al. 2014
SPRED1 Sprouty-related, EVH1 domain-containing protein 1 161742 Q7Z699 Y2H; IP/WB
Hirata Y , et al. 2015
TBPL1 TBP-like 1 9519 P62380 PIP
Chong JA , et al. 2005
TNFSF13B Tumor necrosis factor ligand superfamily member 13B 10673 Q9Y275 IP; LC-MS/MS
Huttlin EL , et al. 2015
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013
TTC1 tetratricopeptide repeat domain 1 7265 Q99614 Y2H
Murthy AE , et al. 1996
Tuba1a tubulin, alpha 1A 22142 P68369 IP; LC-MS/MS
Omrani A , et al. 2015
Tubb4a tubulin, beta 4A class IVA 22153 Q9D6F9 IP; LC-MS/MS
Omrani A , et al. 2015
VSIG1 V-set and immunoglobulin domain-containing protein 1 340547 Q86XK7 IP; LC-MS/MS
Huttlin EL , et al. 2015

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