Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Am J Med Genet A. 2019 Mar;179(3):344-349. doi: 10.1002/ajmg.a.61024. Epub 2019 Jan 13.


Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.

Keywords: DDD study; Primrose syndrome; ZBTB20; exome sequencing; intellectual disability.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / genetics*
  • Calcinosis / diagnosis*
  • Calcinosis / genetics*
  • Child
  • Child, Preschool
  • Ear Diseases / diagnosis*
  • Ear Diseases / genetics*
  • Facies
  • Female
  • Genetic Association Studies*
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Humans
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Muscular Atrophy / diagnosis*
  • Muscular Atrophy / genetics*
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Phenotype*
  • Transcription Factors / genetics*


  • Nerve Tissue Proteins
  • Transcription Factors
  • ZBTB20 protein, human

Supplementary concepts

  • Primrose syndrome