GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome

Am J Hum Genet. 2012 Jun 8;90(6):1088-93. doi: 10.1016/j.ajhg.2012.04.008. Epub 2012 May 10.


Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / pathology
  • Arachnoid Cysts / genetics*
  • Arachnoid Cysts / pathology
  • Brain / abnormalities*
  • Brain / pathology
  • Brain Diseases / genetics*
  • Child
  • Child, Preschool
  • Family Health
  • Female
  • Gene Deletion
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • Homozygote
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Mutation*
  • Sequence Analysis, DNA


  • GPSM2 protein, human
  • Intracellular Signaling Peptides and Proteins

Supplementary concepts

  • Chudley-Mccullough syndrome