TOPORS as a novel causal gene for Joubert syndrome

Am J Med Genet A. 2023 Aug;191(8):2156-2163. doi: 10.1002/ajmg.a.63303. Epub 2023 May 25.


Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%-40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I-binding arginine/serine-rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p.(Pro10Gln)) was identified in individuals with the ciliopathy oral-facial-digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai BioMe biobank, which includes 1880 individuals of Dominican ancestry, supports a high carrier frequency of the TOPORS p.(Pro10Gln) variant in individuals of Dominican descent. Our data nominates TOPORS as a novel causal gene for JBTS and suggests that TOPORS variants should be considered in the differential of ciliopathy-spectrum disease in individuals of Dominican ancestry.

Keywords: TOPORS; ciliopathy; joubert syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • Abnormalities, Multiple* / genetics
  • Abnormalities, Multiple* / metabolism
  • Cerebellum / abnormalities
  • Ciliopathies* / genetics
  • Eye Abnormalities* / diagnosis
  • Eye Abnormalities* / genetics
  • Humans
  • Kidney Diseases, Cystic* / diagnosis
  • Kidney Diseases, Cystic* / genetics
  • Mutation
  • Nervous System Malformations*
  • Retina / abnormalities

Supplementary concepts

  • Agenesis of Cerebellar Vermis