Ciliopathies with Hepatic Involvement the Broad Phenotypical Spectrum of TMEM67 Mutations

Case Study: Ciliopathies are a large group of human disorders caused by dysfunction of the primary cilium. The most important ciliopathies comprise cystic kidney diseases, Joubert syndrome, Meckel–Gruber syndrome and the congenital oculomotor apraxia type Cogan II. Because of major genetic and clinical overlap, a clear cut genotype–phenotype correlation was almost impossible in the past.

Recently TMEM67, encoding the transmembrane protein Meckelin, has been in the scientific focus as a genetic cause of various ciliopathies. Mutations in TMEM67 have been reported for nephronophthisis, Meckel-Gruber syndrome, Joubert syndrome, and COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis hypoplasia, and liver fibrosis). There is a wide range of clinical findings in patients with TMEM67 mutations. However, liver involvement in terms of a congenital hepatic fibrosis has been found as a unifying feature in almost all the patients. This makes TMEM67 one of the first ciliary genes with a relatively strong genotype–phenotype correlation.

We report four patients with mutations in TMEM67 presenting very different clinical phenotypes, one of them showing oculomotor apraxia. To our knowledge, this is the first time that a compound heterozygous TMEM67 mutation is described in a patient with oculomotor apraxia type Cogan II. All four patients present congenital liver fibrosis and elevated liver enzymes, matching the genotype–phenotype correlation described earlier.