A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability

Hammad Yousaf, Shagufta Rehmat, Muhammad Jameel, Rabab Ibrahim, Sohana Nadeem Hashmi, Ehtisham Ul Haq Makhdoom, Justyna Iwaszkiewicz, Saadia Maryam Saadi, Muhammad Tariq, Shahid M. Baig, Mathias Toft, Ambrin Fatima, Zafar Iqbal

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS, OMIM#619150) is an ultra-rare childhood-onset autosomal recessive movement disorder manifesting paroxysmal dyskinesia, global developmental delay, impaired cognition, progressive psychomotor deterioration and/or drug-refractory seizures. We investigated three consanguineous Pakistani families with six affected individuals presenting overlapping phenotypes partially consistent with the reported characteristics of IDDPADS. Whole exome sequencing identified a novel missense variant in Phosphodiesterase 2A (PDE2A): NM_002599.4: c.1514T > C p.(Phe505Ser) that segregated with the disease status of individuals in these families. Retrospectively, we performed haplotype analysis that revealed a 3.16 Mb shared haplotype at 11q13.4 among three families suggesting a founder effect in this region. Moreover, we also observed abnormal mitochondrial morphology in patient fibroblasts compared to controls. Belonging to diverse age groups (13 years-60 years), patients presented paroxysmal dyskinesia, developmental delay, cognitive abnormalities, speech impairment, and drug-refractory seizures with variable onset of disease (as early as 3 months of age to 7 years). Together with the previous reports, we observed that intellectual disability, progressive psychomotor deterioration, and drug-refractory seizures are consistent outcomes of the disease. However, permanent choreodystonia showed variability. We also noticed that the later onset of paroxysmal dyskinesia manifests severe attacks in terms of duration. Being the first report from Pakistan, we add to the clinical and mutation spectrum of PDE2A-related recessive disease raising the total number of patients from six to 12 and variants from five to six. Together, with our findings, the role of PDE2A is strengthened in critical physio-neurological processes.

Original languageEnglish
Pages (from-to)324-333
Number of pages10
JournalClinical Genetics
Issue number3
Publication statusPublished - Sept 2023


  • PDE2A
  • Pakistani population
  • WES
  • consanguinity
  • founder mutation


Dive into the research topics of 'A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability'. Together they form a unique fingerprint.

Cite this