Human Gene Module / Chromosome 9 / STXBP1

STXBP1Syntaxin binding protein 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
22 / 81
Rare Variants / Common Variants
303 / 0
EAGLE Score
19.1
Strong Learn More
Aliases
STXBP1, RP11-56D16.3,  MUNC18-1,  NSEC1,  P67,  RBSEC1,  UNC18
Associated Syndromes
Atypical Rett syndrome, Ohtahara syndrome, Rett syndrome
Chromosome Band
9q34.11
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

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). A de novo missense variant that was predicted to be deleterious (defined as having an MPC score 2) was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified STXBP1 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). An additional de novo loss-of-function variant and a potentially damaging missense variant in the STXBP1 gene were identified in ASD probands from the SPARK cohort in 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 this report identified STXBP1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to STXBP1 (81 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
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 ASD or autistic features
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 -
25 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
26 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Epileptic encephalopathy, ADHD
27 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
28 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test Lionel AC , et al. (2017) No -
29 Support Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1 Suri M , et al. (2017) No Epilepsy/seizures, ASD
30 Support Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes Uddin M , et al. (2017) No ASD, motor delay
31 Recent Recommendation Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy Kovacevic J , et al. (2018) No -
32 Support A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl Yuge K , et al. (2018) No Epilepsy/seizures, developmental regression, ASD,
33 Support Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones Guiberson NGL , et al. (2018) No -
34 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
35 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, ID, epilepsy/seizures, stereotypies
36 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No DD
37 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes -
38 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
39 Support Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes Cogliati F , et al. (2019) No Atypical Rett syndrome/Rett syndrome-like phenotyp
40 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
41 Support Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission Lammertse HCA , et al. (2019) No -
42 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
43 Support Utility of clinical exome sequencing in a complex Emirati pediatric cohort Mahfouz NA et al. (2020) No -
44 Support The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing Wang J et al. (2020) No -
45 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
46 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
47 Support - Brunet T et al. (2021) No -
48 Support - Hiraide T et al. (2021) No -
49 Support - Liu L et al. (2021) No ASD, DD
50 Support - Zou D et al. (2021) No -
51 Support - Pode-Shakked B et al. (2021) No -
52 Support - Mahjani B et al. (2021) Yes -
53 Support - Qaiser F et al. (2021) No -
54 Support - Solgi M et al. (2021) Yes -
55 Support - Yang P et al. (2021) No Autistic features, stereotypy, epilepsy/seizures
56 Support - Xian J et al. (2022) No ASD or autistic behavior
57 Support - Lu Z et al. (2022) No -
58 Support - Hieu NLT et al. (2022) No -
59 Support - Balagura G et al. (2022) No DD, ID, autistic features, stereotypy
60 Support - Naseer MI et al. (2022) No -
61 Support - Hu C et al. (2022) Yes -
62 Recent Recommendation - Stamberger H et al. (2022) No ASD or autistic features, stereotypy
63 Support - Levchenko O et al. (2022) No -
64 Support - Spaull R et al. (2022) Yes -
65 Support - Stenshorne I et al. (2022) No -
66 Recent Recommendation - Zhou X et al. (2022) Yes -
67 Support - Shimelis H et al. (2023) Yes -
68 Support - Sullivan KR et al. (2023) No -
69 Support - Sanchis-Juan A et al. (2023) No ASD, DD, ID
70 Support - Julie Xian et al. (2023) No -
71 Support - Altair Brito Dos Santos et al. (2023) No -
72 Recent Recommendation - Annemiek Arienne van Berkel et al. (2023) No ASD, stereotypy
73 Support - Isaac O Akefe et al. (2024) No -
74 Support - Joo Hyun Kim et al. (2024) No -
75 Support - Purvi Majethia et al. (2024) No ASD, DD
76 Support - Kirsten Furley et al. () No ID, epilepsy/seizures
77 Support - Keiko Gengyo-Ando et al. (2024) No -
78 Support - Ruohao Wu et al. (2024) Yes -
79 Support - Axel Schmidt et al. (2024) No -
80 Support - Soo-Whee Kim et al. (2024) Yes -
81 Support - Nada Amllal et al. (2024) Yes -
Rare Variants   (303)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 35002943 Yang P et al. (2021)
- - copy_number_loss De novo - - 29264391 Uddin M , et al. (2017)
- - copy_number_gain De novo - - 27864847 Parrini E , et al. (2016)
- - copy_number_loss De novo - - 28771251 Lionel AC , et al. (2017)
- - copy_number_gain De novo - - 35655584 Balagura G et al. (2022)
- - copy_number_loss De novo - - 35655584 Balagura G et al. (2022)
- - copy_number_loss De novo - - 26865513 Stamberger H , et al. (2016)
- - copy_number_loss Unknown - - 26865513 Stamberger H , et al. (2016)
c.88-90del - intron_variant Unknown - - 35190816 Xian J et al. (2022)
c.1359+5G>C - intron_variant Unknown - - 35190816 Xian J et al. (2022)
c.84G>A p.Trp28Ter stop_gained Unknown - - 35190816 Xian J et al. (2022)
c.326-2A>G - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.429+1G>A - splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.795-1G>A - splice_site_variant Unknown - - 35190816 Xian J et al. (2022)
c.88-1G>A - splice_site_variant De novo - - 30945278 Jiao Q , et al. (2019)
- - copy_number_loss Unknown - Unknown 22722545 Campbell IM , et al. (2012)
c.1462-2A>G - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1359+1G>A - splice_site_variant Unknown - - 35190816 Xian J et al. (2022)
c.1702+1G>C - splice_site_variant Unknown - - 35190816 Xian J et al. (2022)
c.37+3A>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
del(ACTC) - frameshift_variant De novo - - 21204804 Otsuka M , et al. (2011)
c.1663G>T p.Glu555Ter stop_gained De novo - - 35002943 Yang P et al. (2021)
c.1162C>T p.Arg388Ter stop_gained Unknown - - 35190816 Xian J et al. (2022)
c.1408G>T p.Glu470Ter stop_gained De novo - - 35190816 Xian J et al. (2022)
c.1497C>A p.Tyr499Ter stop_gained Unknown - - 35190816 Xian J et al. (2022)
c.663+1G>T - splice_site_variant De novo - - 29264391 Uddin M , et al. (2017)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.157G>T p.Glu53Ter stop_gained De novo - - 20887364 Saitsu H , et al. (2010)
c.429+1G>A - splice_site_variant De novo - - 20876469 Deprez L , et al. (2010)
c.663+5G>A - splice_site_variant De novo - - 20887364 Saitsu H , et al. (2010)
c.83G>A p.Trp28Ter stop_gained De novo - - 35655584 Balagura G et al. (2022)
c.88-1G>C - splice_site_variant De novo - - 35655584 Balagura G et al. (2022)
c.1099C>T p.Arg367Ter stop_gained De novo - - 29264391 Uddin M , et al. (2017)
c.703C>T p.Arg235Ter stop_gained De novo - - 20887364 Saitsu H , et al. (2010)
c.961A>T p.Lys321Ter stop_gained De novo - - 20887364 Saitsu H , et al. (2010)
c.1029+1G>T - splice_site_variant De novo - - 20876469 Deprez L , et al. (2010)
c.247-?_749+? - copy_number_loss De novo - - 35655584 Balagura G et al. (2022)
c.169+1G>A - splice_site_variant De novo - - 19557857 Hamdan FF , et al. (2009)
c.794+2dup - splice_site_variant De novo - - 35655584 Balagura G et al. (2022)
c.122T>C p.Leu41Pro missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.164T>A p.Ile55Lys missense_variant De novo - - 35190816 Xian J et al. (2022)
c.227T>C p.Leu76Pro missense_variant De novo - - 35190816 Xian J et al. (2022)
c.268G>T p.Asp90Tyr missense_variant De novo - - 35190816 Xian J et al. (2022)
c.1434G>A p.Trp478Ter stop_gained De novo - - 20876469 Deprez L , et al. (2010)
c.420T>A p.Tyr140Ter stop_gained De novo - - 35655584 Balagura G et al. (2022)
c.1359+1G>A - splice_site_variant De novo - - 35655584 Balagura G et al. (2022)
c.1702+1G>C - splice_site_variant De novo - - 35655584 Balagura G et al. (2022)
c.169+2T>C - splice_site_variant De novo - - 31344879 Cogliati F , et al. (2019)
c.1216C>T p.Arg406Cys missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.1627G>C p.Gly543Arg missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.536T>G p.Leu179Arg missense_variant De novo - - 32429945 Wang J et al. (2020)
c.416C>T p.Pro139Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.512G>A p.Arg171His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.568C>T p.Arg190Trp missense_variant De novo - - 33004838 Wang T et al. (2020)
c.569G>A p.Arg190Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.688C>A p.Leu230Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.703C>G p.Arg235Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.568C>T p.Arg190Trp missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.620A>G p.Asp207Gly missense_variant De novo - - 35190816 Xian J et al. (2022)
c.701A>G p.Asp234Gly missense_variant De novo - - 35190816 Xian J et al. (2022)
c.734A>G p.His245Arg missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.847G>A p.Glu283Lys missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.874C>T p.Arg292Cys missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.875G>C p.Arg292Pro missense_variant De novo - - 35190816 Xian J et al. (2022)
(?_-120)_37+?del - copy_number_loss De novo - - 20876469 Deprez L , et al. (2010)
c.1162C>T p.Arg388Ter stop_gained De novo - - 19557857 Hamdan FF , et al. (2009)
c.1099C>T p.Arg367Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.1408G>T p.Glu470Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.1565G>A p.Trp522Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.1162C>T p.Arg388Ter stop_gained De novo - - 35655584 Balagura G et al. (2022)
c.1408G>T p.Glu470Ter stop_gained De novo - - 35655584 Balagura G et al. (2022)
c.1099C>T p.Arg367Ter stop_gained Unknown - - 36475376 Shimelis H et al. (2023)
c.1702+1G>A - splice_site_variant De novo - - 31344879 Cogliati F , et al. (2019)
c.579-1G>C - splice_site_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1061G>A p.Cys354Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1216C>T p.Arg406Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1217G>A p.Arg406His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1548C>A p.Ser516Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1105G>C p.Glu369Gln missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.1194T>G p.Asn398Lys missense_variant De novo - - 35190816 Xian J et al. (2022)
c.1216C>T p.Arg406Cys missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.1217G>A p.Arg406His missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.1324A>G p.Asn442Asp missense_variant De novo - - 35190816 Xian J et al. (2022)
c.1651C>T p.Arg551Cys missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.1652G>A p.Arg551His missense_variant Unknown - - 35190816 Xian J et al. (2022)
c.1705T>C p.Ser569Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1197C>A p.Val399= synonymous_variant De novo - - 35190816 Xian J et al. (2022)
c.533C>T p.Thr178Ile missense_variant De novo - - 28944233 Suri M , et al. (2017)
c.568C>T p.Arg190Trp missense_variant De novo - - 28944233 Suri M , et al. (2017)
c.874C>T p.Arg292Cys missense_variant De novo - - 34840252 Solgi M et al. (2021)
c.17T>A p.Leu6His missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1099C>T p.Arg367Ter stop_gained De novo - - 31344879 Cogliati F , et al. (2019)
c.1359+1G>A - splice_site_variant De novo - - 35851549 Stamberger H et al. (2022)
c.107T>A p.Leu36Ter stop_gained De novo - - 26865513 Stamberger H , et al. (2016)
c.430-1G>C - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.579-2A>G - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.794+5G>A - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.795-2A>T - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.902+1G>A - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1433G>A p.Trp478Ter stop_gained De novo - Simplex 33951346 Liu L et al. (2021)
c.1651C>T p.Arg551Cys missense_variant De novo - - 28944233 Suri M , et al. (2017)
c.1702G>A p.Gly568Ser missense_variant De novo - - 31139143 Long S , et al. (2019)
c.755T>C p.Met252Thr missense_variant De novo - - 29264391 Uddin M , et al. (2017)
c.874C>T p.Arg292Cys missense_variant De novo - - 29264391 Uddin M , et al. (2017)
c.251T>A p.Val84Asp missense_variant De novo - - 18469812 Saitsu H , et al. (2008)
c.1099C>T p.Arg367Ter stop_gained De novo - - 26918652 Yamashita S , et al. (2016)
c.1387G>T p.Glu463Ter stop_gained De novo - - 35851549 Stamberger H et al. (2022)
c.1099C>T p.Arg367Ter stop_gained De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.364C>T p.Arg122Ter stop_gained De novo - - 26865513 Stamberger H , et al. (2016)
c.922A>T p.Lys308Ter stop_gained De novo - - 26865513 Stamberger H , et al. (2016)
c.326-327del - frameshift_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1110+1G>A - splice_site_variant Unknown - - 26865513 Stamberger H , et al. (2016)
c.1359+1G>A - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1359+5G>C - splice_site_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1082C>T p.Thr361Ile missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.1706C>T p.Ser569Phe missense_variant De novo - - 28708303 Chrot E , et al. (2017)
- p.Lys526AsnfsTer23 frameshift_variant De novo - - 29264391 Uddin M , et al. (2017)
c.247-1del - splice_site_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.794+5G>C - splice_site_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.539G>A p.Cys180Tyr missense_variant De novo - - 18469812 Saitsu H , et al. (2008)
c.1075C>T p.Gln359Ter stop_gained De novo - - 26865513 Stamberger H , et al. (2016)
c.1099C>T p.Arg367Ter 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>A - splice_site_variant De novo - - 38374498 Purvi Majethia et al. (2024)
c.1328T>G p.Met443Arg missense_variant De novo - - 18469812 Saitsu H , et al. (2008)
c.1631G>A p.Gly544Asp missense_variant Unknown - - 18469812 Saitsu H , et al. (2008)
c.1217G>A p.Arg406His missense_variant De novo - - 20887364 Saitsu H , et al. (2010)
c.1654T>C p.Cys552Arg missense_variant De novo - - 21204804 Otsuka M , et al. (2011)
c.1115T>G p.Leu372Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1651C>T p.Arg551Cys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.755T>C p.Met252Thr missense_variant De novo - - 28771251 Lionel AC , et al. (2017)
c.416C>T p.Pro139Leu missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.569G>A p.Arg190Gln missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.751G>A p.Ala251Thr missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.875G>A p.Arg292His missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.87+1G>T - splice_site_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
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.17T>C p.Leu6Pro missense_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.217G>C p.Ala73Pro missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.1261G>T p.Glu421Ter stop_gained De novo - Unknown 33619735 Brunet T et al. (2021)
c.1029+1G>A - splice_site_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1216C>T p.Arg406Cys missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1216C>T p.Arg406Cys missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1217G>A p.Arg406His missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1249G>C p.Gly417Arg missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1268T>C p.Leu423Pro missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1324A>G p.Asn442Asp missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1461G>C p.Glu487Asp missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1651C>T p.Arg551Cys missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1652G>A p.Arg551His missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1652G>T p.Arg551Leu missense_variant De novo - - 35655584 Balagura G et al. (2022)
c.1438C>T p.Pro480Ser missense_variant Unknown - - 38536866 Kirsten Furley et al. ()
c.568C>T p.Arg190Trp missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.416C>T p.Pro139Leu missense_variant De novo - - 31344879 Cogliati F , et al. (2019)
c.767T>C p.Leu256Pro missense_variant De novo - - 31344879 Cogliati F , et al. (2019)
c.122T>C p.Leu41Pro missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.902+5G>A - splice_site_variant Familial Paternal - 21062273 Saitsu H , et al. (2010)
c.1060T>C p.Cys354Arg missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1630G>T p.Gly544Cys missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.1708A>G p.Thr570Ala missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1216C>T p.Arg406Cys missense_variant De novo - - 31344879 Cogliati F , et al. (2019)
c.416C>T p.Pro139Leu missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.569G>A p.Arg190Gln missense_variant Unknown - - 35851549 Stamberger H et al. (2022)
c.874C>T p.Arg292Cys missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.416C>T p.Pro139Leu missense_variant Unknown - - 35979408 Stenshorne I et al. (2022)
c.735T>G p.His245Gln missense_variant De novo - - 35979408 Stenshorne I et al. (2022)
c.88-1G>C - splice_site_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.703C>T p.Arg235Ter stop_gained De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.560C>T p.Pro187Leu missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.128_130del p.Ser43del inframe_deletion De novo - - 35655584 Balagura G et al. (2022)
c.1206del p.Tyr402Ter frameshift_variant De novo - - 21364700 Hamdan FF , et al. (2011)
c.1099C>T p.Arg367Ter stop_gained De novo - Simplex 32382396 Mahfouz NA et al. (2020)
c.1334A>C p.His445Pro missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.1630G>T p.Gly544Cys missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.1645G>A p.Glu549Lys missense_variant De novo - - 35851549 Stamberger H et al. (2022)
c.1217G>A p.Arg406His missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.325+5G>A - splice_site_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.518C>A p.Ala173Glu 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.704G>A p.Arg235Gln missense_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.874C>T p.Arg292Cys 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.875G>T p.Arg292Leu missense_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.931dup p.Ser311PhefsTer3 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.987del p.Met330CysfsTer2 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.585C>A p.Tyr195Ter stop_gained Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.60del p.Lys21ArgfsTer16 frameshift_variant De novo - - 29544889 Yuge K , et al. (2018)
c.751G>A p.Ala251Thr missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.175G>A p.Glu59Lys missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.38-2A>G p.? splice_site_variant De novo - Simplex 39359953 Nada Amllal et al. (2024)
c.364C>T p.Arg122Ter stop_gained De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.901C>T p.Gln301Ter stop_gained De novo - Simplex 35851549 Stamberger H et al. (2022)
c.1022T>C p.Leu341Pro 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.1217G>A p.Arg406His missense_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1277T>C p.Leu426Pro 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.1651C>T p.Arg551Cys missense_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.1723C>T p.Pro575Ser missense_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1595G>A p.Arg532His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1651C>T p.Arg551Cys missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.1651C>T p.Arg551Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1461G>A p.Glu487= synonymous_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.795-1G>A - splice_site_variant De novo - Simplex 26865513 Stamberger H , et al. (2016)
c.785A>T p.Asp262Val missense_variant De novo - - 38374498 Purvi Majethia et al. (2024)
c.1162C>T p.Arg388Ter stop_gained De novo - - 27184330 Gburek-Augustat J , et al. (2016)
c.512G>A p.Arg171His missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.551del p.Lys184ArgfsTer21 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.717del p.Ser240AlafsTer8 frameshift_variant De novo - - 28944233 Suri M , et al. (2017)
c.1651C>T p.Arg551Cys missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.301G>C p.Ala101Pro missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.568C>T p.Arg190Trp missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.998_1000del p.Lys333del inframe_deletion De novo - - 35655584 Balagura G et al. (2022)
c.1162C>T p.Arg388Ter stop_gained De novo - Simplex 35851549 Stamberger H et al. (2022)
c.703C>T p.Arg235Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.1217G>A p.Arg406His missense_variant De novo - - 38374498 Purvi Majethia et al. (2024)
c.1606del p.Arg536AlafsTer10 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.517G>A p.Ala173Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1004C>T p.Pro335Leu missense_variant De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.1277T>C p.Leu426Pro missense_variant De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.305C>A p.Ala102Glu missense_variant De novo - Simplex 35663845 Naseer MI et al. (2022)
c.1249+1G>A - splice_site_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1359+1G>T - splice_site_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.747dup p.Gln250SerfsTer6 frameshift_variant De novo - - 20887364 Saitsu H , et al. (2010)
c.1651C>T p.Arg551Cys missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.1060T>C p.Cys354Arg missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.1439C>T p.Pro480Leu missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1099C>T p.Arg367Ter stop_gained Familial Maternal - 35851549 Stamberger H et al. (2022)
c.770_772dup p.Leu257dup inframe_insertion De novo - - 35851549 Stamberger H et al. (2022)
c.1548-6_1559delinsAT - frameshift_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.568C>T p.Arg190Trp missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.334_335del p.Asp112CysfsTer4 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.875G>A p.Arg292His missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.1004C>T p.Pro335Leu missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1217G>A p.Arg406His 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.57_59del p.Ile19_Lys20delinsMet inframe_deletion Unknown - - 35190816 Xian J et al. (2022)
c.62_64del p.Lys21_Val22delinsIle inframe_deletion De novo - - 35190816 Xian J et al. (2022)
c.388_389del p.Leu130AspfsTer11 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.897_898del p.Ser300ProfsTer13 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.897_898del p.Ser300ProfsTer13 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.695_696del p.Ile232ThrfsTer6 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.1783T>C p.Ter595GlnextTer67 stop_lost Unknown - Multiplex 35937496 Spaull R et al. (2022)
c.1265del p.Asn422ThrfsTer2 frameshift_variant De novo - - 35655584 Balagura G et al. (2022)
c.701A>G p.Asp234Gly missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.734A>G p.His245Arg missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.758G>A p.Ser253Asn missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.847G>A p.Glu283Lys missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.1171_1172del p.Val391ProfsTer12 frameshift_variant Unknown - - 34145886 Zou D et al. (2021)
c.57_59del p.Ile19_Lys20delinsMet inframe_indel De novo - - 35655584 Balagura G et al. (2022)
c.1216C>T p.Arg406Cys missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.1651C>T p.Arg551Cys missense_variant De novo - Simplex 35851549 Stamberger H et al. (2022)
c.430-2_432delinsTGGGAGA - frameshift_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.236C>T p.Pro79Leu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
- p.Ser241fs frameshift_variant De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.913dup p.Arg305ProfsTer9 frameshift_variant Familial Maternal - 35741772 Hu C et al. (2022)
c.1205_1206insG p.Tyr402Ter frameshift_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.1501_1519del p.Tyr501LeufsTer39 frameshift_variant Unknown - - 35190816 Xian J et al. (2022)
c.1154del p.Asp385AlafsTer30 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1217G>A p.Arg406His missense_variant De novo - Simplex 25714420 Romaniello R , et al. (2015)
c.1060T>C p.Cys354Arg missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.569G>A p.Arg190Gln missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.791A>G p.Tyr264Cys missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.893_894del p.Glu298GlyfsTer15 frameshift_variant Unknown - - 20876469 Deprez L , et al. (2010)
c.388_389del p.Leu130AspfsTer11 frameshift_variant De novo - - 20887364 Saitsu H , et al. (2010)
c.364C>T p.Arg122Ter stop_gained De novo - Extended multiplex 35663845 Naseer MI et al. (2022)
c.1672del p.Gln558ArgfsTer9 frameshift_variant De novo - - 26865513 Stamberger H , et al. (2016)
c.1651C>T p.Arg551Cys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1216C>G p.Arg406Gly missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.703C>T p.Arg235Ter stop_gained De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.1359+5G>C - splice_site_variant De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.1301del p.Pro434ArgfsTer112 frameshift_variant De novo - Simplex 33951346 Liu L et al. (2021)
NM_003165.6:c.963+?_(*1967+?) del - copy_number_loss De novo - - 20876469 Deprez L , et al. (2010)
c.1282del p.Gln428SerfsTer118 frameshift_variant De novo - - 35851549 Stamberger H et al. (2022)
c.1598G>C p.Ser533Thr missense_variant Familial Paternal - 28628100 Geisheker MR , et al. (2017)
c.1058_1061del p.Asp353ValfsTer2 frameshift_variant De novo - - 35655584 Balagura G et al. (2022)
c.847G>A p.Glu283Lys missense_variant Unknown Not maternal - 35851549 Stamberger H et al. (2022)
c.570G>A p.Arg190%3D splice_site_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.57_59del p.Ile19_Lys20delinsMet frameshift_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1095_1096del p.Cys366ProfsTer13 frameshift_variant De novo - - 35655584 Balagura G et al. (2022)
c.874C>T p.Arg292Cys missense_variant Unknown Not maternal - 26865513 Stamberger H , et al. (2016)
c.1598G>C p.Ser533Thr missense_variant Unknown Not maternal - 28628100 Geisheker MR , et al. (2017)
c.1583del p.Pro528GlnfsTer18 frameshift_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.568C>T p.Arg190Trp missense_variant De novo - Multi-generational 31130284 Monies D , et al. (2019)
c.620A>G p.Asp207Gly missense_variant De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.704G>A p.Arg235Gln missense_variant De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.785A>T p.Asp262Val missense_variant De novo - - 38298782 Annemiek Arienne van Berkel et al. (2023)
c.1651C>T p.Arg551Cys missense_variant Unknown - Multi-generational 31130284 Monies D , et al. (2019)
c.360dup p.Ser121IlefsTer21 frameshift_variant Unknown - Simplex 35851549 Stamberger H et al. (2022)
NM_003165.3:c.38_?_(663+?_902+?)del - copy_number_loss De novo - - 26865513 Stamberger H , et al. (2016)
c.1659del p.Tyr554ThrfsTer3 frameshift_variant Unknown Not maternal - 25914188 Olson HE , et al. (2015)
c.578+1G>A - splice_site_variant De novo - Multiplex (monozygotic twins) 35655584 Balagura G et al. (2022)
c.778G>T p.Glu260Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1099C>T p.Arg367Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.875G>A p.Arg292His missense_variant De novo - Multiplex (monozygotic twins) 34622207 Qaiser F et al. (2021)
c.1336C>T p.Leu446Phe missense_variant Familial Both parents Multiplex 31855252 Lammertse HCA , et al. (2019)
c.704G>A p.Arg235Gln missense_variant 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.1315A>T p.Ile439Phe missense_variant De novo (germline mosaicism) - Multiplex 35851549 Stamberger H et al. (2022)
c.148dup p.Ile50AsnfsTer14 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.438del p.Leu147TrpfsTer18 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

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."

4/1/2021
1
icon
1

Score remained at 1

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).

Reports Added
[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021]
1/1/2021
1
icon
1

Score remained at 1

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).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Utility of clinical exome sequencing in a complex Emirati pediatric cohort2020] [The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing2020]
1/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
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).

Reports Added
[New Scoring Scheme]
7/1/2019
3S
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3S

Decreased from 3S to 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).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
3S
icon
3S

Decreased from 3S to 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).

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019] [The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
10/1/2018
3S
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3S

Decreased from 3S to 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).

Reports Added
[Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
3S
icon
3S

Decreased from 3S to 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).

Reports Added
[Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1.2017]
7/1/2017
3S
icon
3S

Decreased from 3S to 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).

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017] [Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017] [Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.2017]
1/1/2017
3S
icon
3S

Decreased from 3S to 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).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
10/1/2016
3S
icon
3S

Decreased from 3S to 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).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
4/1/2016
3S
icon
3S

Decreased from 3S to 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). 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).

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.2008] [Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.2010] [STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.2010] [Paternal mosaicism of an STXBP1 mutation in OS.2010] [STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.2009] [Intellectual disability without epilepsy associated with STXBP1 disruption.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.2016] [A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.2015] [Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.2015] [Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy.2016] [Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome.2016]
1/1/2016
icon
3S

Increased from to 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). 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).

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.2008] [Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.2010] [STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.2010] [Paternal mosaicism of an STXBP1 mutation in OS.2010] [STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.2009] [Intellectual disability without epilepsy associated with STXBP1 disruption.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.2016] [A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.2015] [Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.2015] [Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy.2016]
Krishnan Probability Score

Score 0.5751140747065

Ranking 659/25841 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 0.99988294322709

Ranking 702/18225 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 0.75457231068876

Ranking 1601/18665 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
Larsen Cumulative Evidence Score

Score 5

Ranking 293/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.20850596125832

Ranking 4140/20870 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
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