Classic Joubert syndrome is characterized by distinctive cerebellar and brain stem malformation called the “molar tooth sign”, hypotonia and developmental delays. The designation “Joubert syndrome and related disorders (JSRD)” is used to describe patients with additional findings, including kidney disease, liver disease, retinal dystrophy, ocular colobomas, oral hamartomas, endocrine abnormalities, Hirschsprung's disease and a plethora of other disorders.

While aforementioned clinical categories remain important for choosing adequate diagnostic tests and providing prognostic information, it must be emphasized that Joubert syndrome represents a genetic disorder. Thus identifying the gene mutations involved in the development of this disease is crucial for diagnostic, prenatal and carrier testing, as well as accurate recurrence risk counseling.

Gene mutations and defective cilia

Joubert syndrome and related disorders are caused by biallelic mutations in at least 19 genes. The following designations have been assigned to implicated genes (listed in a random order): TMEM67 (MKS3), NPHP1, CEP290 (NPHP6), CC2D2A, AHI1, RPGRIP1L, KIF7, ARL13B, INPP5E, TMEM216, TCTN1, TCTN2, TMEM237, OFD1, CEP41, C5orf42, TMEM138, TMEM231 and TCTN3.

Products of those genes are proteins known or suspected to play roles in specific cell structures called cilia. Cilia are microscopic, membrane-bound, hair-like structures that project from the surface of cells and are involved in chemical signaling. They are very important for the structure of most cell types, including brain cells (neurons) and certain cells in the liver and kidneys.

Mutations in the genes associated with Joubert syndrome and related disorders result in problems with the structure and function of cilia. As a result, important chemical signaling pathways are disrupted during development. Still, although it is believed that defective cilia are responsible for most of the features present in this disorder, it is still unclear how they lead to specific developmental abnormalities.

The strongest correlation to date between specific gene changes and subsequent expression of the disease is between MKS3 mutations and clinically apparent liver disorder (portal hypertension, elevated transaminases and liver fibrosis). Therefore all patients with Joubert syndrome and liver disease should be tested for MKS3 mutations.

Correlations between genotype and phenotype involving other genes are not as strong, but are increasingly demonstrated in the literature. For example, affected individuals with NPHP1 deletions invariably manifest renal disease and milder form of brain malformation. Also, a majority of subjects with AHI1 mutations have retinal dystrophy; however, renal disease occurs in only fraction of them.

Inheritance of Joubert Syndrome

Joubert syndrome has an autosomal recessive pattern of inheritance, which means both copies of a gene in each cell are struck with a mutation. The parents of the affected individual with such autosomal recessive condition each carry one copy of the mutated gene, but they do not show signs and symptoms of the condition.

At conception, each sibling of an affected individual has a 25% chance of getting the condition if the autosomal recessive pattern of inheritance is responsible for the disease. Also, there is a 50% chance of being an asymptomatic carrier, and a 25% chance of not being affected by the disease and not being a carrier.

Rare cases of Joubert syndrome are inherited in an X-linked recessive pattern (such as JSRD caused by mutation of OFD1 gene). The causative gene is located on the X chromosome in those cases, which is one of the two sex chromosomes.

As males have only one X chromosome, one altered copy of the gene in each cell is sufficient to result with this condition. In females, a mutation would have to occur in both copies of the gene to cause the syndrome, as they carry two X chromosomes. Therefore males are affected by X-linked Joubert syndrome much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Since not all mutations are yet identified in patients with Joubert syndrome (as well as in patients with JSRD), prenatal diagnosis is still limited to a subset of families. In such cases fetal ultrasound and fetal magnetic resonance imaging can be very useful in at-risk pregnancies.