ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 5q11.2-q12.1
  • GRCh37/hg19 chr5: 58,264,865-59,783,925
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr5: 58,969,038-60,488,098
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000005.9) (NC_000005.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

The current evidence for haploinsufficiency of PDE4D is insufficient at this time. Missense variants in PDE4D have described in patients with acrodysostosis; these variants are thought to cause this phenotype via a dominant negative mechanism (see OMIM 600129 for a summary). Furthermore, although some studies (referenced below) suggest PDE4D may contribute to the phenotypic findings of patients with 5q11.2-5q12.1 deletions, focal PDE4D deletion and other loss-of-function-type mutations have not yet been reported. Lindstrand et al. (2014) (PMID:24203977) reported three individuals with structural variants involving PDE4D, in addition to five PDE4D missense variants in patients with acrodysostosis. The structural variants were identified from a cohort of patients referred for clinical testing by array CGH: 2 patients carried deletions (approximately 8 and 10 kb in size) encompassing PDE4D and additional genes, and one patient (originally identified through the DECIPHER database) had a de novo intragenic duplication of exons 2-6. The authors were unable to clone the breakpoints of the duplication by PCR and noted that it is possible this alteration is benign, although in silico prediction suggested either duplication orientation would result in a frameshift for all but one PDE4D isoform. Clinical findings in these patients included low BMI, long fingers, toes, and extremities, prominent noses and mild intellectual disability-the authors posited many of these findings may represent a "mirror" phenotype to those of patients with acrodysostosis. The authors also reviewed the patients described by Jaillard et al. 2011 (PMID: 21594994), who reported additional patients with large deletions of 5q12.1 (including PDE4D and other genes) and similar phenotypes, and who provided experimental evidence for dosage effects on development in zebrafish. Although the literature suggests possible PDE4D haploinsufficiency, due to the lack of focal alterations affecting PDE4D and the insufficient evidence for pathogenicity of the single intragenic PDE4D duplication, the current haploinsufficiency score for PDE4D is 0.

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