Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome

Eur J Hum Genet. 2018 Sep;26(9):1266-1271. doi: 10.1038/s41431-018-0183-6. Epub 2018 Jun 11.


A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles*
  • Codon, Nonsense
  • Heterozygote
  • Humans
  • Hypopituitarism / genetics*
  • Hypopituitarism / pathology
  • Male
  • Membrane Proteins / genetics*
  • Mutation, Missense
  • Phenotype*
  • RNA Splicing
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology


  • Codon, Nonsense
  • Membrane Proteins
  • TMEM67 protein, human

Supplementary concepts

  • RHYNS syndrome