ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000021.8) (NC_000021.9)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Multiple mutations in APP are associated with familial early onset Alzheimer disease. Most described mutations are expected to result in gain of function (persistance or mislocalization/ toxic buildup of this protein). No gross gene deletions were found at the time of this literature search.

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
16921174 Sleegers et al (2006) reported a focal APP gene duplication segregating in a large, multigenerational Dutch family with dominantly inherited early-onset Alzheimer disease. Additionally, a similar duplication involving only the APP gene was reported in this paper in an unrelated individual from the same geographical area with early-onset Alzheimer disease.

Triplosensitivity phenotype comment:

Increased gene dosage of APP is thought to be linked to dominantly inherited early onset Alzheimer disease. Rovelet-Lecrux et al (2006; PMID: 16369530): APP gene duplication segregating in multiple families with dominantly inherited early-onset Alzheimer disease with cerebral amyloid angiopathy. All 5 of these duplications included other genes on 21q. See also PMID: 16959815 for more phenotypic detail on these five families. Kasuga et al (2009; PMID:19684239): Describes 2 unrelated Japanese families with APP duplications and early-onset Alzheimer disease. These duplications also included other genes on 21q.