STXBP1Syntaxin binding protein 1

Score

Suggestive Evidence, Syndromic Criteria 3.1, Syndromic

Autism Reports / Total Reports

5 / 24

Rare Variants / Common Variants

109 / 0

Aliases

STXBP1, RP11-56D16.3, MUNC18-1, NSEC1, P67, RBSEC1, UNC18

Associated Syndromes

Atypical Rett syndrome, Ohtahara syndrome

Genetic Category

Rare Single Gene Mutation, Syndromic

Chromosome Band

9q34.11

Associated Disorders

ASD, EPS, DD/NDD, ADHD, ID, EP

Relevance to Autism

A 67 kb monogenic deletion affecting exons 1-4 of the STXBP1 gene was identified in a female patient with ASD, severe ID, and neonatal seizures (Campbell et al., 2012).

Molecular Function

This gene encodes a syntaxin-binding protein that appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Defects in STXBP1 are the cause of epileptic encephalopathy early infantile type 4 (EIEE4) [MIM:612164]. Affected individuals have neonatal or infantile onset of seizures, suppression-burst pattern on EEG, profound mental retardation, and MRI evidence of hypomyelination.

External Links

Gene Card Entrez Gene OMIM UniProt

Reports (24)
Variants (109)
Gene Score
Associated CNVs (1)

Reports related to STXBP1 (24 Reports)

#	Type	Title	Author, Year	Autism Report	Associated Disorders
1	Highly cited	De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.	Saitsu H , et al. (2008)	No	ID
2	Support	De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.	Hamdan FF , et al. (2009)	No	Epilepsy
3	Support	Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.	Deprez L , et al. (2010)	No	ID
4	Support	STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.	Saitsu H , et al. (2010)	No	-
5	Support	Paternal mosaicism of an STXBP1 mutation in OS.	Saitsu H , et al. (2010)	No	-
6	Support	STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study.	Otsuka M , et al. (2011)	No	-
7	Support	Intellectual disability without epilepsy associated with STXBP1 disruption.	Hamdan FF , et al. (2011)	No	-
8	Support	Patterns and rates of exonic de novo mutations in autism spectrum disorders.	Neale BM , et al. (2012)	Yes	-
9	Primary	Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.	Campbell IM , et al. (2012)	Yes	-
10	Support	Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.	Rauch A , et al. (2012)	No	Epilepsy, ASD
11	Support	Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.	Carvill GL , et al. (2013)	No	ID, ASD, DD
12	Positive association	De novo mutations in epileptic encephalopathies.	Epi4K Consortium , et al. (2013)	No	IS, LGS, DD, ID, ASD, ADHD
13	Support	Large-scale discovery of novel genetic causes of developmental disorders.	Deciphering Developmental Disorders Study (2014)	No	ASD (1 case)
14	Support	Whole-genome sequencing of quartet families with autism spectrum disorder.	Yuen RK , et al. (2015)	Yes	-
15	Support	A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.	Romaniello R , et al. (2015)	No	ID, epilepsy/seizures
16	Support	Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.	Olson HE , et al. (2015)	No	Epilepsy
17	Recent recommendation	Incorporating Functional Information in Tests of Excess De Novo Mutational Load.	Jiang Y , et al. (2015)	No	-
18	Support	Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.	Zhang Y , et al. (2015)	No	-
19	Recent recommendation	STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.	Stamberger H , et al. (2016)	No	Autism (2 cases), autistic features (12 cases)
20	Support	Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy.	Yamashita S , et al. (2016)	No	Epilepsy
21	Support	Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome.	Gburek-Augustat J , et al. (2016)	No	Ataxia
22	Support	De novo genic mutations among a Chinese autism spectrum disorder cohort.	Wang T , et al. (2016)	Yes	-
23	Support	Clinical exome sequencing: results from 2819 samples reflecting 1000 families.	Trujillano D , et al. (2016)	Yes	-
24	Support	Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.	Parrini E , et al. (2016)	No	-

Rare Variants (109)

Allele Change	Residue Change	Variant Type	Inheritance Pattern	Parental Transmission	Family Type	PubMed ID	Author, Year
c.1631G>A	p.Gly544Asp	missense_variant	Unknown	-	-	18469812	Saitsu H , et al. (2008)
c.539G>A	p.Cys180Tyr	missense_variant	De novo	-	-	18469812	Saitsu H , et al. (2008)
c.1328T>G	p.Met443Arg	missense_variant	De novo	-	-	18469812	Saitsu H , et al. (2008)
c.251T>A	p.Val84Asp	missense_variant	De novo	-	-	18469812	Saitsu H , et al. (2008)
c.1162C>T	p.Arg388Ter	stop_gained	De novo	-	-	19557857	Hamdan FF , et al. (2009)
c.169+1G>A	-	splice_site_variant	De novo	-	-	19557857	Hamdan FF , et al. (2009)
c.1434G>A	p.Trp478Ter	stop_gained	De novo	-	-	20876469	Deprez L , et al. (2010)
c.893_894delAG	p.Glu278GlyfsTer15	frameshift_variant	Unknown	-	-	20876469	Deprez L , et al. (2010)
c.1029 + 1G>T	p.[Lys343AsnfsTer13; Tyr344_Glu603del Ins11]	splice_site_variant	De novo	-	-	20876469	Deprez L , et al. (2010)
c.963 + ?_(*1967+?) del	p.Thr322_Glu603 del	copy_number_loss	De novo	-	-	20876469	Deprez L , et al. (2010)
(?_-120)_37 + ?del	-	copy_number_loss	De novo	-	-	20876469	Deprez L , et al. (2010)
c.429 + 1G>A	-	splice_site_variant	De novo	-	-	20876469	Deprez L , et al. (2010)
c.1217G>A	p.Arg406His	missense_variant	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.157G>T	p.Glu53Ter	stop_gained	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.388_389delCT	p.Leu130AspfsTer11	frameshift_variant	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.663 + 5G>A	-	splice_site_variant	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.703C>T	p.Arg235Ter	stop_gained	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.747dupT	p.Gln250SerfsTer6	frameshift_variant	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.961A>T	p.Lys321Ter	stop_gained	De novo	-	-	20887364	Saitsu H , et al. (2010)
c.902+5G>A	-	splice_site_variant	Familial	Paternal	-	21062273	Saitsu H , et al. (2010)
del(ACTC)	-	frameshift_variant	De novo	-	-	21204804	Otsuka M , et al. (2011)
c.1654T>C	p.Cys552Arg	missense_variant	De novo	-	-	21204804	Otsuka M , et al. (2011)
c.1206delT	p.Tyr402Ter	frameshift_variant	De novo	-	-	21364700	Hamdan FF , et al. (2011)
c.1651C>T	P.Arg551Cys	missense_variant	De novo	-	Simplex	22495311	Neale BM , et al. (2012)
-	-	copy_number_loss	Unknown	-	Unknown	22722545	Campbell IM , et al. (2012)
c.301G>C	p.Ala101Pro	missense_variant	De novo	-	Simplex	23020937	Rauch A , et al. (2012)
c.247Ã¢â¬Â1delG	p.?	splice_site_variant	De novo	-	Simplex	23020937	Rauch A , et al. (2012)
c.175G>A	p.Glu59Lys	missense_variant	De novo	-	Simplex	23020937	Rauch A , et al. (2012)
c.1154delC	p.Met387TyrfsTer17	frameshift_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.1630G>T	p.Gly544Cys	missense_variant	Unknown	-	-	23708187	Carvill GL , et al. (2013)
c.125C>T	p.Ser42Phe	missense_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.238T>C	p.Ser80Pro	missense_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.568C>T	p.Arg190Trp	missense_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.1060T>C	p.Cys354Arg	missense_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.1708A>G	p.Thr570Ala	missense_variant	De novo	-	-	23708187	Carvill GL , et al. (2013)
c.1004C>T	p.Pro335Leu	missense_variant	De novo	-	-	23934111	Epi4K Consortium , et al. (2013)
c.703C>T	p.Arg235Ter	stop_gained	De novo	-	-	23934111	Epi4K Consortium , et al. (2013)
c.1217G>A	p.Arg406His	missense_variant	De novo	-	-	23934111	Epi4K Consortium , et al. (2013)
c.568C>T	p.Arg190Trp	missense_variant	De novo	-	-	23934111	Epi4K Consortium , et al. (2013)
c.1631G>A	p.Gly544Asp	missense_variant	De novo	-	-	23934111	Epi4K Consortium , et al. (2013)
c.1099C>T	p.Arg367Ter	stop_gained	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.148dupA	p.Ile50AsnfsTer14	frameshift_variant	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.704G>A	p.Arg235Gln	missense_variant	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.437_438delCCinsC	p.Leu147TrpfsTer18	frameshift_variant	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.778G>T	p.Glu260Ter	stop_gained	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.1631G>T	p.Gly544Val	missense_variant	De novo	-	Simplex	25533962	Deciphering Developmental Disorders Study (2014)
c.1580delC	p.Pro528GlnfsTer18	frameshift_variant	De novo	-	Multiplex	25621899	Yuen RK , et al. (2015)
c.1217G>A	p.Arg406His	missense_variant	De novo	-	Simplex	25714420	Romaniello R , et al. (2015)
c.1658delC	p.Tyr554ThrfsTer3	frameshift_variant	Unknown	Not maternal	-	25914188	Olson HE , et al. (2015)
c.568C>T	p.Arg190Trp	missense_variant	De novo	-	Simplex	26544041	Zhang Y , et al. (2015)
c.568C>T	p.Arg190Trp	missense_variant	De novo	-	Simplex	26544041	Zhang Y , et al. (2015)
c.1022T>C	p.Leu341Pro	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.704G>A	p.Arg235Gln	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1216C>T	p.Arg406Cys	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.922A>T	p.Lys308Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1075C>T	p.Gln359Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1217G>A	p.Arg406His	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.875G>A	p.Arg292His	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1277 T>C	Leu426Pro	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1099C>T	Arg367Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1651C>T	p.Arg551Cys	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1438C>T	p.Pro480Ser	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.364C>T	p.Arg122Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1359+1 G>A	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
-	-	copy_number_loss	Unknown	-	-	26865513	Stamberger H , et al. (2016)
c.364C>T	p.Arg122Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.430-1G>C	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.38-?_(663+?_902+?) del	-	copy_number_loss	De novo	-	-	26865513	Stamberger H , et al. (2016)
-	-	copy_number_loss	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1723C>T	p.Pro575Ser	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1548-6_1559delinsAT	p.?	frameshift_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.794+5G>A	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.795-2A>T	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.388-389delCT	-	frameshift_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
-	-	copy_number_loss	Unknown	-	-	26865513	Stamberger H , et al. (2016)
c.874C>T	p.Arg292Cys	missense_variant	Unknown	Not maternal	-	26865513	Stamberger H , et al. (2016)
c.874C>T	p.Arg292Cys	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1651C>T	p.Arg551Cys	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1461G>A	p.(=)	synonymous_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.17T>C	p.Leu6Pro	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.518C>A	p.Ala173Glu	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1110+1G>A	-	splice_site_variant	Unknown	-	-	26865513	Stamberger H , et al. (2016)
c.902+1G>A	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.107T>A	p.Leu36Ter	stop_gained	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1565G>A	p.Trp522Ter	stop_gained	Unknown	-	-	26865513	Stamberger H , et al. (2016)
c.1359+5G>C	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1672delC	p.Gln558ArgfsTer	frameshift_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.1652G>A	p.Arg551His	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.579-2A>G	p.?	splice_site_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.430-2_430+2delinsTGGGAGA	p.?	frameshift_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.874C>T	p.Arg292Cys	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
-	-	copy_number_loss	Unknown	-	-	26865513	Stamberger H , et al. (2016)
c.875G>A	p.Arg292His	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.875G>T	p.Arg292Leu	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.703C>G	p.Arg235Gly	missense_variant	De novo	-	-	26865513	Stamberger H , et al. (2016)
c.795-1G>A	p.?	splice_site_variant	De novo	-	Simplex	26865513	Stamberger H , et al. (2016)
c.1099C>T	p.Arg367Ter	stop_gained	De novo	-	-	26918652	Yamashita S , et al. (2016)
c.1162C>T	p.Arg388Ter	stop_gained	De novo	-	-	27184330	Gburek-Augustat J , et al. (2016)
c.695_696del	p.Ile232ThrfsTer6	frameshift_variant	De novo	-	-	27824329	Wang T , et al. (2016)
c.517G>A	p.Ala173Thr	missense_variant	Familial	Paternal	-	27824329	Wang T , et al. (2016)
c.585C>A	p.Tyr195Ter	stop_gained	Unknown	Not maternal	-	27824329	Wang T , et al. (2016)
c.703C>T	p.Arg235Ter	stop_gained	De novo	-	Simplex	27848944	Trujillano D , et al. (2016)
c.1060T>C	p.Cys354Arg	missense_variant	De novo	-	Simplex	27848944	Trujillano D , et al. (2016)
c.1565G>A	p.Trp522Ter	stop_gained	De novo	-	-	27864847	Parrini E , et al. (2016)
c.57_59del	p.Ile19_Lys20delinsMet	frameshift_variant	De novo	-	-	27864847	Parrini E , et al. (2016)
c.1408G>T	p.Glu470Ter	stop_gained	De novo	-	-	27864847	Parrini E , et al. (2016)
c.1099C>T	p.Arg367Ter	stop_gained	De novo	-	-	27864847	Parrini E , et al. (2016)
c.1216C>T	p.Arg406Cys	missense_variant	De novo	-	-	27864847	Parrini E , et al. (2016)
-	-	copy_number_gain	De novo	-	-	27864847	Parrini E , et al. (2016)

Common Variants

No common variants reported.

Current Score
Scoring History

SFARI Gene score

Suggestive Evidence, Syndromic

Heterozygous variants in the STXBP1 gene are responsible for a form of early-onset epileptic encephalopathy (EIEE4; OMIM 612164) highlighted by epilepsy and often severe intellectual disability (Saitsu et al., 2008; Deprez et al., 2010). ASD has been observed in individuals with STXBP1 variants both in the presence and absence of epilepsy and/or intellectual disability (Campbell et al., 2012; Neale et al., 2012; Deciphering Developmental Disorders Study, 2015; Yuen et al., 2015; Wang et al., 2016). A systemic review of 147 patients with STXBP1 encephalopathy, including 45 previously unreported patients, demonstrated that autism or autistic features were observed in approximately 20% of published cases, although the actual number of cases with autism/autistic features may be greater due to the focus of most studies on the intellectual disability/epilepsy phenotype (Stamberger et al., 2016). Variants in STXBP1 have also been identified in patients presenting with atypical Rett syndrome, with affected individuals frequently exhibiting autistic features and stereotyped movements (Romaniello et al., 2015; Olson et al., 2015).

criteria met

See SFARI Gene'scoring criteria

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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."

04-01-2017

Initial score established: 3S

Description


9q34.11	Total Reports 12	CNV Type Deletion-Duplication	Case Populations / Individuals 22 / 44

Human Gene Module / Chromosome 9 / STXBP1