Comprehensive genotype-phenotype correlation in AP-4 deficiency syndrome; Adding data from a large cohort of Iranian patients

Clin Genet. 2021 Jan;99(1):187-192. doi: 10.1111/cge.13845. Epub 2020 Sep 14.


Mutations in adaptor protein complex-4 (AP-4) genes have first been identified in 2009, causing a phenotype termed as AP-4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype-phenotype correlation of the AP-4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease-causing variants in AP-4 complex subunits, using next-generation sequencing. Furthermore, by comparing genotype-phenotype findings of those affected individuals with previously reported patients, we further refine the genotype-phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP-4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.

Keywords: AP-4 deficiency syndrome; Iranian families; consanguinity; genotype-phenotype correlation; intellectual disability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 4 / deficiency
  • Adaptor Protein Complex 4 / genetics*
  • Adolescent
  • Brain / metabolism
  • Brain / pathology
  • Child
  • Child, Preschool
  • Cohort Studies
  • Corpus Callosum / diagnostic imaging
  • Corpus Callosum / pathology
  • Female
  • Genetic Association Studies*
  • Humans
  • Intellectual Disability / diagnostic imaging
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Iran / epidemiology
  • Male
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Quadriplegia / diagnostic imaging
  • Quadriplegia / genetics*
  • Quadriplegia / pathology


  • Adaptor Protein Complex 4