ClinGen Dosage Sensitivity Curation Page

15q11q13 recurrent (PWS/AS) region (BP1-BP3, Class 1)

  • Curation Status: Complete
  • id: ISCA-37404
  • Date last evaluated: 2013-11-26
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

  • 15q11.2-q13.1
  • GRCh37/hg19 chr15: 22,832,519-28,379,874
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr15: 22,782,170-28,134,728
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000015.9) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
7611294 Christian et al. (1997) characterized the two proximal breakpoints in 80 individuals with either Angelman or Prader-Willi syndrome. 44% were shown to have the class I deletion, while 56% were found to have the class II deletion (45/80). No phenotypic difference between class I and class II deletions were noted.
22045295 Kim et al. (2012) describe 88 patients with Prader-Willi syndrome, 32 had the type I deletion (36%), 49 had the type II deletion (56%) and the remaining 7 had atypical deletions.

Haploinsufficiency phenotype comments:

Deletions of 15q11q13 are seen in approximately 70% of both Angelman syndrome (AS) and Prader-Willi syndrome (PWS) patients, with deletions of the maternal allele causing AS and deletions of the paternal allele causing PWS. These deletions are divided into Class I and Class II deletions depending on the proximal breakpoint location. The phenotypes in individuals with class I and class II deletions are largely indistinguishable, although recent studies have proposed behavioral differences between individuals with Class I vs. Class II deletions (PMID: 14993551). Please see GeneReviews entry for comprehensive discussions of both Prader Willi and Angelman syndromes (http://www.ncbi.nlm.nih.gov/books/NBK1330/; http://www.ncbi.nlm.nih.gov/books/NBK1144/) Of note: Schaaf et al. (2013) recently published a series of individuals with Prader-Willi-like phenotypes and truncating mutations on the paternal allele of MAGEL2, a gene within the PWS region (PMID: 24076603)

Evidence for gain of function phenotype
PubMed ID Description
9106540 Cook et al. (1997) describe a family in which two children with autism spectrum disorders inherited a 15q11-q13 duplication from their reportedly normal mother. The duplication was found to have arisen de novo on the mother's paternally inherited allele. A third child who was reportedly unaffected did not inherit the duplication.
18374305 Christian et al. (2008) identified three maternally inherited 15q11-q13 duplications amongst a cohort of 397 unrelated individuals with autism spectrum disorders.
16840569 Jacquemont et al. (2006) identified one de novo 15q11-q13 duplication, derived from the maternal allele, in a female with autism and mild intellectual disability

Triplosensitivity phenotype comment:

Duplication 15q11-q13 has been associated with autism, intellectual disability, seizures, and psychiatric disorders, such as schizophrenia (PMID: 21324950). Evidence suggests a parent-of-origin effect, with maternally-derived duplications being more frequently associated with abnormal phenotypes. Paternally-derived duplications have been reported mostly in unaffected individuals, though they have been identified in some individuals with abnormal phenotypes, including autism (Urraca et al. 2013, PMID: 23495136) and seizures (Marini et al. 2013, PMID: 23633446), though the findings have not been consistent. It has been suggested that there have been an insufficient number of cases reported to establish a relationship between paternally-derived duplications and phenotypes (Hogart et al. 2010, PMID: 18840528). Urraca et al. 2013 describe a cohort of 14 individuals with interstitial duplications, including Class I and Class II duplications. It appeared that size of the duplication did not correlate with severity of the phenotype. They also note that some phenotypic characteristics of isodicentric 15q (idic 15q) subjects, who are tetrasomic for the BP2-BP3 region, overlap with those of the interstitial duplication individuals in the study. Individuals with the interstitial duplications, however, have a more subtle phenotype, implying a gene dosage effect.