ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27824329 Wang et al. (2016) reported a re-sequencing study of 1,543 Chinese probands with autistic spectrum disorder (ASD) by targeting 189 risk genes. The study found one female (PatientID: M23139) with a de novo splice donor mutation involving SHANK1 gene (c.2458+1G>A). Apart from ASD, this patient also had moderate ID, developmental delay (motor & speech), typical regression, sleep problems, attention problems and anxiety. Notably, there were five other patients with a paternally inherited missense variant found within SHANK1 gene (PatientID: M20570, M26951, M19541, M26757 and M8656).

Haploinsufficiency phenotype comments:

Fromer et al. (2014) (PMID: 24463507) reported a study of 623 schizophrenia patients, where one female patient (ProbandID: 2400-1) had a de novo frameshift mutation in SHANK1 gene. Grozeva et al. (2015) (PMID: 26350204) reported a study of 1,000 patients with intellectual disability using targeted next-generation sequencing analysis. The study showed twelve samples with mutation in the SHANK1 gene of unknown inheritance. There were ten missense variants (UK10K_FINDWGA SampleID: 5410694, 5410827, 5410959, 5410965, 5411014, 5411060, 5411144, 5411179, 5411502, 5411511) and two frameshift variants (UK10K_FINDWGA SampleID: 5410809 and 5410842) . Sato et al. (2012) (PMID: 22503632) reported seven individuals with a small deletion involving SHANK1 gene. In a cohort of 1,158 Canadian autistic patients. six individuals (all from family 1) had a 63.8 kb heterozygous deletion (exons 1-20) involving the SHANK1 gene. The deletion also included the entire CLEC11A gene. Three males (III-5, IV-1 and IV-3) had autistic spectrum disorder. The fourth male (I-1) had a broader autism phenotype. Two of the males (III-5 and IV-3) had an additional truncating mutation (Tyr313*) in the PCDHGA11 gene. The same deletion was also found in two females (II-4 and III-2) in this family who had no autistic feature but were shy and anxious. The author suggested reduced penetrance in female carriers. In another cohort of 456 European autistic patients, there was a male (II-1 of family 2) found to have a de novo 63.4 kb heterozygous deletion (exons 20-23) involving the SHANK1 gene. The deletion also included the entire SYT3 gene. The maternal half-sister with autism did not carry the deletion. Collins and Galvez (2018) (PMID: 30053575) suggested that mice with shRNA-mediated neocortical SHANK1 knockdown (50% reduction in SHANK1 protein level) was significantly impaired in the forebrain-dependent associative learning task when compared to control. There were three entries in the database of genomic variants (DGV): nsv1072893 - deletion of exon 23 (Thareja et al 2015; PMID: 25765185); nsv953605 - deletion of exon 23 (Doga et al 2014; PMID: 24416366); esv3583462 - deletion of introns 7-14 (Uddin et al 2014; PMID: 25503493).

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