Human Gene Module / Chromosome 18 / ASXL3

ASXL3Additional sex combs like 3 (Drosophila)

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
5 / 12
Rare Variants / Common Variants
48 / 0
Aliases
ASXL3, KIAA1713
Associated Syndromes
Bainbridge-Ropers syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
18q12.1
Associated Disorders
ASD, ID, DD/NDD
Relevance to Autism

A de novo heterozygous frameshift variant in the ASXL3 gene was identified in a six-year-old nonverbal female with autism, global developmental delay, microcephaly, and metopic craniosynostosis (Dinwiddie et al., 2013).

Molecular Function

Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility. Heterozygous de novo truncating variants in this gene were recently identified in patients with a novel clinical phenotype similar to Bohring-Opitz syndrome (Bainbridge et al., 2013).

Reports related to ASXL3 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Bainbridge MN , et al. (2013) No ID (1 case)
2 Primary De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. Dinwiddie DL , et al. (2013) Yes DD
3 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
5 Support De novo Dominant ASXL3 Mutations Alter H2A Deubiquitination and Transcription in Bainbridge-Ropers Syndrome. Srivastava A , et al. (2015) No DD, ID
6 Support Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Hori I , et al. (2016) No ASD, DD
7 Support Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Kuechler A , et al. (2016) No ID
8 Recent recommendation Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 ... Balasubramanian M , et al. (2017) No ID, ASD/autistic features (9/12 cases)
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
10 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
11 Support Global developmental delay and postnatal microcephaly: Bainbridge-Ropers syndrome with a new mutation in ASXL3. Contreras-Capetillo SN , et al. (2017) No DD, microcephaly
12 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
Rare Variants   (48)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1210C>T p.Gln404Ter stop_gained De novo - - 23383720 Bainbridge MN , et al. (2013)
c.1396C>T p.Gln466Ter stop_gained De novo - - 23383720 Bainbridge MN , et al. (2013)
c.1975_1978del p.Thr659fsTer41 frameshift_variant De novo - - 23383720 Bainbridge MN , et al. (2013)
insT p.Pro474fs frameshift_variant De novo - - 23383720 Bainbridge MN , et al. (2013)
c.1897_1898delCA p.Gln633ValfsTer13 frameshift_variant De novo - Simplex 24044690 Dinwiddie DL , et al. (2013)
c.3106C>T p.Arg1036Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
ins(T) - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.4817G>A p.Arg1606Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5309G>A p.Gly1770Glu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5468G>A p.Arg1823Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6737T>C p.Val2246Ala missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2773C>G p.His925Asp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3407A>G p.Lys1136Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2396C>T p.Ser799Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6724G>T p.Val2242Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2153C>T p.Pro718Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4466T>A p.Val1489Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6374A>G p.Tyr2125Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.182A>T p.Asn61Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.274G>A p.Gly92Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2923T>G p.Cys975Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1448dupT p.Thr484AsnfsTer5 frameshift_variant De novo - - 26647312 Srivastava A , et al. (2015)
c.4330T>C p.Arg1444Ter stop_gained Unknown Not maternal - 26647312 Srivastava A , et al. (2015)
c.3364C>T p.Gln1122Ter stop_gained De novo - - 26647312 Srivastava A , et al. (2015)
c.3039+1G>A p.? splice_site_variant De novo - - 27075689 Hori I , et al. (2016)
c.1219delA p.Ser407AlafsTer2 frameshift_variant De novo - - 27901041 Kuechler A , et al. (2016)
c.1369G>T p.Glu457Ter stop_gained De novo - - 27901041 Kuechler A , et al. (2016)
c.3106C>T p.Arg1036Ter stop_gained De novo - - 27901041 Kuechler A , et al. (2016)
c.3494_3495delGT p.Cys1165Ter frameshift_variant De novo - - 27901041 Kuechler A , et al. (2016)
c.3613G>T p.Glu1205Ter stop_gained De novo - - 27901041 Kuechler A , et al. (2016)
c.4072_4073delGT p.Val1358LeufsTer8 frameshift_variant De novo - - 27901041 Kuechler A , et al. (2016)
c.4330C>T p.Arg1444Ter stop_gained De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1201del p.Ala401GlnfsTer8 frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1074T>A p.Tyr358Ter stop_gained De novo - - 28100473 Balasubramanian M , et al. (2017)
c.4144C>T p.Gln1382Ter stop_gained De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1783C>T p.Gln595Ter stop_gained De novo - - 28100473 Balasubramanian M , et al. (2017)
c.3355dup p.His1119ProfsTer7 frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1082dup p.Leu362AlafsTer23 frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.3635T>G p.Leu1212Ter stop_gained De novo - - 28100473 Balasubramanian M , et al. (2017)
c.3127_3128dup p.Gly1045ValfsTer99 frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.3178dup p.Arg1060ProfsTer50 frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1484insTGAA p.Asp497Ter frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.1491dup p.Asn498Ter frameshift_variant De novo - - 28100473 Balasubramanian M , et al. (2017)
c.4906C>T p.Gln1636Ter stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.4219_4220del p.Leu1407fs frameshift_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.2992_2995del p.Glu998fs frameshift_variant De novo - - 28431838 Contreras-Capetillo SN , et al. (2017)
c.1682C>A p.Ser561Ter stop_gained Unknown - - 28554332 Bowling KM , et al. (2017)
c.6640T>C p.Ser2214Pro missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Three de novo LoF variants in the ASXL3 gene have been identified in ASD probands (PMIDs 24044690, 25363760). De novo truncating variants in this gene have also been identified in individuals presenting with a syndrome that shares characteristics with Bohring-Opitz syndrome, including developmental delay, post-natal growth retardation and feeding problems (PMID 23383720). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASXL3 as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Balasubramanian et al., 2017 reported 12 new patients with de novo heterozygous loss-of-function variants in ASXL3 and a diagnosis of Bainbridge-Ropers syndrome; nine of these patients were either formally diagnosed with autism or ASD, or were described as having autistic features.

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.

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
1S

Initial score established: 1S

Description

Three de novo LoF variants in the ASXL3 gene have been identified in ASD probands (PMIDs 24044690, 25363760). De novo truncating variants in this gene have also been identified in individuals presenting with a syndrome that shares characteristics with Bohring-Opitz syndrome, including developmental delay, post-natal growth retardation and feeding problems (PMID 23383720). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASXL3 as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Balasubramanian et al., 2017 reported 12 new patients with de novo heterozygous loss-of-function variants in ASXL3 and a diagnosis of Bainbridge-Ropers syndrome; nine of these patients were either formally diagnosed with autism or ASD, or were described as having autistic features.

CNVs associated with ASXL3(1 CNVs)
18q12.1 16 Deletion-Duplication 26  /  88
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) Human Protein Binding 8314 Q92560
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