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 the 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.
Family Raises Awareness for Joubert Syndrome
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: 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 that are 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. Cilia are very important for the structure of most cell types, including neurons, as well as 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. 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 disorders such as 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 a milder form of brain malformations. Also, a majority of subjects with AHI1 mutations have retinal dystrophy; however, renal disease occurs in only a fraction of them.
Inheritance of Joubert syndrome
Joubert syndrome has an autosomal recessive pattern of inheritance, which means that 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 any signs or 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 in 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.
Not all mutations have been identified in patients with Joubert syndrome, as well as in patients with JSRD); therefore, prenatal diagnosis remains limited to a subset of families. In such cases, fetal ultrasound and fetal magnetic resonance imaging (MRI) can be very useful in at-risk pregnancies.