Human Gene Module / Chromosome 9 / STXBP1

STXBP1Syntaxin binding protein 1

Score
3S
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.

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)
Status 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.247‐1delG 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.

SFARI Gene score
3S

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).

3

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.

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
3S

Initial score established: 3S

Description

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).

CNVs associated with STXBP1(1 CNVs)
9q34.11 12 Deletion-Duplication 22  /  44
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