Expanding the clinical phenotype and genetic spectrum of PURA-related neurodevelopmental disorders

Brain Dev. 2021 Oct;43(9):912-918. doi: 10.1016/j.braindev.2021.05.009. Epub 2021 Jun 8.


Background: PURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 deletion syndrome and PURA syndrome. PURA-NDDs are characterized by neonatal hypotonia, moderate to severe global developmental delay/intellectual disability (GDD/ID), facial dysmorphism, epileptic seizures, nonepileptic movement disorders, and ophthalmological problems. PURA-NDDs have recently been identified and underestimated in neurodevelopmental cohorts, but their diagnosis is still challenging.

Methods: We retrospectively reviewed the clinical characteristics, genetic spectrum, and diagnostic journey of patients with PURA-NDDs.

Results: We report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding difficulties (4/5, 80%), and respiratory problems (4/7, 57%) in the neonatal period. All of them had severe GDD/ID and could not achieve independent walking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual fixation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no significant differences in clinical phenotypes between 5q31.3 microdeletion syndrome and PURA syndrome. PURA-NDDs need to be considered as a differential diagnosis in individuals who show severe hypotonia, including feeding difficulties since birth and severe developmental retardation with distinctive facial and ophthalmological features.

Conclusions: Our data expands the phenotypic and genetic spectrum of PURA-NDD. Next-generation sequencing methods based on the detailed phenotypic evaluation would shorten the diagnostic delay and would help this rare disorder become a recognizable cause of neurodevelopmental delay.

Keywords: 5q31.3 microdeletion syndrome; Global developmental delay and intellectual disability (GDD/ID); PURA; PURA neurodevelopmental disorders; PURA syndrome.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Deletion
  • DNA-Binding Proteins / genetics*
  • Face
  • Female
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Muscle Hypotonia / genetics
  • Neurodevelopmental Disorders / diagnosis*
  • Neurodevelopmental Disorders / genetics*
  • Phenotype
  • Retrospective Studies
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • PURA protein, human
  • Transcription Factors