PPP1R21-related syndromic intellectual disability: Report of an adult patient and review

Sara Loddo, Viola Alesi, Francesca Clementina Radio, Silvia Genovese, Silvia Di Tommaso, Giusy Calvieri, Valeria Orlando, Enrico Bertini, Maria Lisa Dentici, Antonio Novelli, Bruno Dallapiccola

Research output: Contribution to journalArticlepeer-review


Variants in PPP1R21 were recently found to be associated with an autosomal recessive intellectual disability syndrome in 9 individuals. Our patient, the oldest among the known subjects affected by PPP1R21-related syndrome, manifested intellectual disability, short stature, congenital ataxia with cerebellar vermis hypoplasia, generalized hypertrichosis, ulcerative keratitis, muscle weakness, progressive coarse appearance, macroglossia with fissured tongue, and deep palmar and plantar creases. We provide an overview of the clinical spectrum and natural history of this newly recognized disorder, arguing the emerging notion that PPP1R21 gene mutations could result in endolysosomal functional defects. The oldest patients could display a more severe clinical outcome, due to accumulation of metabolites or damage secondary to an alteration of the autophagy pathway. Follow-up of patients with PPP1R21 mutations is recommended for improving the understanding of PPP1R21-related syndromic intellectual disability.

Original languageEnglish
Pages (from-to)3014-3022
Number of pages9
JournalAmerican Journal of Medical Genetics, Part A
Issue number12
Publication statusPublished - Dec 2020


  • homozygous mutation
  • neurodevelopmental disorder
  • PPP1R21
  • PPP1R21-related syndrome
  • storage disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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