Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis

Am J Med Genet A. 2021 Mar;185(3):884-888. doi: 10.1002/ajmg.a.62020. Epub 2020 Dec 27.


We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.

Keywords: PACS1; PACS2; WDR37; coloboma; intellectual disability.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Amino Acid Substitution
  • Cerebellum / abnormalities
  • Choroid / abnormalities*
  • Coloboma / genetics*
  • Craniofacial Abnormalities / genetics
  • Cryptorchidism / genetics
  • Face / abnormalities
  • Genetic Association Studies
  • Hearing Loss, Sensorineural / genetics
  • Heart Defects, Congenital / genetics
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics
  • Iris / abnormalities*
  • Male
  • Mutation, Missense
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Point Mutation
  • Seizures / genetics
  • Syndrome
  • Vesicular Transport Proteins / deficiency
  • Vesicular Transport Proteins / genetics*
  • Young Adult


  • Nuclear Proteins
  • PACS1 protein, human
  • PACS2 protein, human
  • Vesicular Transport Proteins
  • WDR37 protein, human