• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
AUTS2 (HGNC:14262) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
activator of transcription and developmental regulator AUTS2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
KIAA0442, FBRSL2
%HI
0.51(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.25(Read more about gnomAD LOEUF score)
Cytoband
7q11.22
Genomic Coordinates
GRCh37/hg19: chr7:69063461-70258492 NCBI Ensembl UCSC
GRCh38/hg38: chr7:69598475-70793506 NCBI Ensembl UCSC
MANE Select Transcript
NM_015570.4 ENST00000342771.10 (Read more about MANE Select)
Function
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:25519132). The PRC1-like complex that contains PCGF5, RNF2, CSNK2B, RYBP and AUTS2 has decreas... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-22359
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
06/24/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • autism spectrum disorder due to AUTS2 deficiency Monarch
HI Evidence:
  • PUBMED: 22872102
    Nagamani et al (2013) reported four patients from 3 unrelated families with small CNVs ranging in size between 133-319 kb that disrupted AUTS2. One proband with developmental delay had a de novo deletion involving multiple exons. A second proband with developmental delay was also found to have a multi-exon deletion; however, complete inheritance information was unavailable (the variant was shown not to be inherited from the mother, but the father was unavailable for testing). Two siblings with developmental delay were also described; these individuals were found to have a duplication involving exon 5, predicted to be in-frame, inherited from a mother with microcephaly and mild intellectual disability (ID). The CNVs were detected by an exon-targeted array CGH with dense oligonucleotide coverage in exons of genes known or hypothesized to be causative of multiple human phenotypes.
  • PUBMED: 23332918
    Beunders et al (2013) identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus amongst a cohort of 49,684 individuals with developmental delays and/or multiple congenital anomalies. No microdeletions involving an AUTS2 exon were detected amongst 16, 784 controls. The authors showed that this "was highly significant (p = 0.00092), [and] suggest[ed] that exonic disruptions of AUTS2 give rise to a highly penetrant phenotype in humans. This [was] supported by CNV data from the latest version of the Database of Genomic Variants (August 25, 2012), wherein none of the array-based studies show CNVs that disrupt an exon, and by the fact that none of the 24 probands with an exonic AUTS2 deletion had a rare de novo CNV at another locus." Phenotype information was only available for 17 of the 24 individuals with deletions involving at least one exon of AUTS2. Probands were said to be affected with variable neurodevelopmental phenotypes, including ID, developmental delay, and autism, as well as microcephaly, dysmorphic features, and short stature. Eight of these 17 cases were found to be de novo. Of these 8 cases, two were part of more complex rearrangements (one inversion, one translocation) with additional breakpoints in other areas of the genome that were not further studied. Another two cases were whole gene deletions that also involved one or more other genes. Of the remaining 4 de novo cases, one was said to be an in-frame deletion of exons 6-11; no functional studies were performed on this specific variant to determine its effect on the underlying protein. Three of the 17 cases with detailed phenotype information were inherited. One (case 1) was inherited from an apparently normal father. The other two (cases 4 and 6) were inherited from affected mothers. In case 4, an in-frame deletion of exons 3-4 was inherited from a mother said to have "learning difficulties." In case 6, a frameshifting deletion of exons 5-6 was inherited from a mother with "mild ID." The authors proposed that "several lines of evidence support the causality of AUTS2 deletions for this broad phenotypic spectrum; these are (1) the significant enrichment of exonic deletions in cases, (2) the fact that auts2 zebrafish morphants show microcephaly and smaller lower-jaw size comparable to the human phenotype (these aberrant phenotypes can be fully rescued by both full-length and short 3′ human AUTS2 transcript), (3) the fact that no individuals with an exonic deletion had a second rare de novo CNV, and (4) the fact that all exonic deletions were de novo or inherited from an affected parent except for the in-frame exon 2 deletion of case 1."
  • PUBMED: 23650183
    Jolley et al (2013) reported a de novo intragenic deletion, detected by chromosomal microarray, of 683–806 kb AUTS2 deletion involving multiple exons (3-6) in a male patient with developmental delay, intellectual disability, short stature, ptosis, and mild dysmorphism. This deletion is predicted to result in a frameshift resulting in premature truncation at exon 7.
HI Evidence Comments:
Additional information includes: PMID 25106414: Asadollahi et al. (2014) report their experience with small, exonic copy number variants in a cohort of 714 individuals with neurodevelopmental disorders. In the supplemental material, they describe patient 58822, a male with mild developmental delay, growth deficiency, and microcephaly. He as found to have an in-frame deletion of exon 4, which was determined to be inherited from his father. The authors classify the father as "affected," and describe him as having relative short stature as compared to his parents and siblings. PMID 31788251: Saeki et al. (2019) describe a de novo heterozygous AUTS2 variant (c.1464_1467delACTC, p.Tyr488*) identified by trio-based exome sequencing in a Japanese male with developmental delay, autism, short stature, microcephaly, and history of cleft lip and palate. This variant is predicted to result in a frameshift and truncated protein. PMID 25205402: Beunders et al. (2015) describe two previously unreported, unrelated adult males with de novo heterozygous variants in AUTS2. Proband 1 was tested via trio-based exome sequencing and found to have a frameshift variant in exon 7 (c.857_858delAA, p.Lys286fs). Proband 2 was tested via SNP array and found to have an intragenic deletion involving exon 6, predicted to result in frameshift and premature truncation of the protein. Both individuals were described as having intellectual disability, autism, microcephaly, and history of feeding difficulties. PMID 26545289: Fan et al. (2016) describe 2 additional de novo deletions involving exon 6 (predicted to result in frameshift and truncated protein) in Chinese individuals with developmental delay and dysmorphic features. A third individual was also described, but their deletion includes genes other than AUTS2. All variants were detected by array. PMID 24459036: Amarillo et al. (2014) describe an individual with a de novo 62kb deletion involving exon 6 (predicted to result in frameshift and truncated protein) in an individual with severe speech/language delay and history of tonic-clonic movements. The variant was detected on SNP array. AUTS2 is suggested to play a critical role in early brain development and its association with intellectual disability, autism spectrum disorders (ASDs), and other neurodevelopmental disorders (NDDS). Genomic rearrangements and copy number aberrations involving AUTS2 have been implicated in a clinical spectrum of NDDS with and without congenital malformations and dysmorphic features (mostly de novo). There are at least 11 de novo, putative loss of function, intragenic deletions in individuals with neurodevelopmental disorders, reaching the scoring threshold for a haploinsufficiency score of 3. Inherited and in-frame variants have also been reported (some are documented here), but were not necessary to reach this final score. Additional cases are also available in the literature.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000007.13) (NC_000007.14)