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
23832105 Liao C (2013): these study reported two de novo deletions and one missense mutation (c.1153A > C, p.Met385Leu in exon 11) in familial microcephalic patients. (1) A de novo heterozygous 336-bp deletion [153,649,777?153,985,995 (GRCh37/hg19)] in the DPP6 gene was identified by CMA in a 12-year-old boy with microcephaly and ID (MRD33; 616311), (2) A de novo heterozygous 362-bp [153,829,386?154,191,684(GRCh37/hg19)]deletion in the DPP6 gene was identified by CMA in a 15-year-old girl with microcephaly and ID (MRD33; 616311), Both deletions were de novo and harboured the DPP6 gene only. Further RT-PCR were performed to confirm the deletions. (3) A missense mutation (c.1153A > C, p.Met385Leu in exon 11) was identified by Sanger sequencing in a 5-year-old girl from a family segregating autosomal dominant ID and microcephaly (MRD33; 616311). Her mother, maternal aunt, and grandfather were also affected and mutation identified. The mutation, which segregated with disease in the family, was not identified in 100 unrelated healthy controls.
18252227 Marshall CR et. al., 2008. In table 2 and 3, there is one patient with de novo deletion involving DPP6. NA0002-000, a de novo 66kb exonic deletion (hg19: 153,585,000-153,651,462) of DPP6 in a patient with IQ/LOF unknown, severely delayed receptive language and expressive language, severe repetitive behaviors, no dysmorphism.
30874922 Cacace et al. 2019. An inversion of 4 Mb disrupting the DPP6 sequence was detected in the linked 7q36 locus (mapped the two breakpoints on chr7:149,704,610?153,786,893), segregating on the disease haplotype and explaining the linkage in family 1270. Seven affected family members had AD inherited early-onset Alzheimer?s Disease. Of note, the phenotype is inconsistent with other publications, and inversion may affect other gene?s function.

Haploinsufficiency phenotype comments:

Copy number variants and rearrangement breakpoints involving the gene DPP6 have been identified in association with several clinical phenotypes, including syndromic microcephaly (with short stature, intellectual disability, and language deficits), autism, and Gilles de la Tourette syndrome (PMID: 25129042). A total of 3 patients with ID were reported with de novo deletions of DPP6 exons (Liao and Marshall, described above). Additionally, Cacace et al. 2019 reported 7 affected members of a family with early-onset Alzheimer's disease and an inversion with one breakpoint within DPP6; however, it is unclear how the inversion may be affecting the function of other genes involved. Cacace et al. also reported two unrelated individuals with frontotemporal dementia were also found to have nonsense variants in DPP6; at this time, it is unclear how the dementia/Alzheimer's phenotype may relate to the intellectual disability phenotype. In cases where parental testing was performed, both de novo and inherited alterations have been identified, in some cases from an unaffected parent. There is also some common copy number variation overlapping exons of the DPP6, as documented in the Database of Genomic Variants (see DGV:, and the gnomAD pLI score for this gene is 0.34, with an observed/expected ratio of 0.23 (95% CI 0.14-0.38) (June 2019). Additional evidence is needed in order to determine the role of DPP6 haploinsufficiency in human phenotypes.

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