ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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."
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.

Haploinsufficiency phenotype 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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity