ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24381304 Lionel AC et al. (2014) reported 46 exonic deletions (one is full gene deletion) in clinical microarray data from a cohort of 89985 individuals across 10 sites including 64114 subjects with neurodevelopmental disorders (NDDs). Deletions near the 3? terminus of ASTN2, which disrupt multiple ASTN2 isoforms, were significantly enriched in the NDD subjects compared with 44085 population-based controls (p=0.002). Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). Ten deletions were inherited from the mother, eight deletions from the father, two arose de novo and 25 unknown inheritance. There were also 12 exonic duplications in ASTN2 gene, five of them maternally inherited, two paternally inherited and the rest five unknown inheritance. None had other CNVs. The duplications in ASTN2 did not significantly differ from the cases and cohorts.
32094338 Husson et al. (2020) reported one patient (pt 365) from a cohort of 253 ASD subjects including 68 patients with ASD and intellectual disability (ID) and 90 with Asperger syndrome. This individual had an exonic deletion (exon 1-4) of 123kb in ASTN2 gene. It is maternally inherited and the mother has Asperger syndrome. Sibling carrying this CNV also has Asperger syndrome.
21832240 Lionel AC et al. (2011) reported 19 rare inherited CNVs from a 248 unrelated ADHD probands, two of these CNVs are exonic deletions of 177kb and 148 kb in ASTN2 gene, respectively. CNVs at this locus were absent in 2357 population-based controls. This study also tested for rare CNVs in a newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD and found CNVs partially overlapping ASTN2 in four ASD (~1%) and two ADHD probands (~1%). The exonic deletions of ASTN2 yielded the strongest association with ADHD and ASD.
19809473 Bernardini L et al. (2010) reported one patient with an exonic deletion of 0.545Mb in ASTN2 from a cohort of 70 patients referred to the diagnostic laboratory for CNVs analysis in the 2006?2007 period. This CNV was not present in his mother, whereas the father?s DNA was not available. It is not present on 270 control samples from International HapMap Project.
18940311 Vrijenhoek T et al. (2008) screened 54 schizophrenic patients with, one exonic deletion of 98kb in ASTN2 gene was identified in one patient (patient 4). A partial duplication of ASTN2 was found in another cohort of 752 patients. These CNVs were not found in 706 unaffected control individuals. These results suggest disruption of the ASTN2 gene might have functional consequences.

Haploinsufficiency phenotype comments:

ASTN2 has at least 3 isoforms. TRIM23 is a small two exon gene two-exon gene nested within an intron of the long isoform of ASTN2, which is transcribed from the opposite strand to ASTN2. The first exons of TRIM32 and the ASTN2 shorter isoforms are only 39 bp apart. TRIM32 encodes an ubiquitin ligase and is expressed at high levels in a wide range of tissues, including the brain, muscle and skeletal tissue. Homozygous point mutations in this gene have been implicated in autosomal recessive disorders such as limb-girdle muscular dystrophy and Bardet?Biedl syndrome. The latter is a heterogeneous multi-system disorder presenting with retinopathy, obesity and cognitive impairment, among other symptoms. Frequent phenotypes observed in cases with CNVs involving exons of ASTN2 gene only present a wide range of neurodevelopmental disorder (NDD) including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD), moderate intellectual disability (ID), dysmorphisms, hypotonia, seizures, obesity, bilateral cryptorchidism and caf?-au ?lait spots. Though there have been multiple reports of putative loss of function variants in this gene among individuals with a wide variety of NDD presentations (as well as other phenotypes), there have also been multiple reports of these variants being identified in unaffected parents and/or population controls. The role that ASTN2 plays in NDD (and its relative penetrance) is unclear at this time. Additional evidence includes: PMID: 19404257 Glessner JT et al., (2009) reported rare CNVs including one exonic deletion in ASTN2 were enriched in ASD cases compared to controls (P = 9.5 ? 10?3) in whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry. This exonic deletion in ASTN2 (case 4) was identified in this 859 ASD cohort.

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