Joubert syndrome is a phenotypically heterogeneous ciliopathy classically defined by brain anomalies such as cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa. These findings give the appearance of a molar tooth sign on a brain MRI. JBTS6 also results in neurological problems such as delayed psychomotor development, intellectual disability, ataxia and hypotonia. Other symptoms include breathing dysregulation, renal defects such as nephronophthisis, microcysts and renal failure, liver abnormalities such as hepatic fibrosis and bile duct proliferation, and ophthalmological impairments such as oculomotor apraxia, chorioretinal coloboma and blindness.
The disorder does not appear to have a gender or racial bias and is found to affect between 1/80,000 to 1/100,000 live births. Joubert syndrome is congenital and has an onset in infancy. Prognosis depends on the severity of the cerebellar vermis hypoplasia as well as the extent of multi-organ involvement. While some children may have mild forms of the disorder, others suffer from severe motor disability and critical organ failure. Treatment is currently symptomatic and supportive. Patients may benefit from physical, occupational and speech therapy as well as infant stimulation.
Al-Hamed et al. (2016) examined a cohort of 44 Saudi families affected by antenatal cystic kidney disease. In one consanguineous family, the fetus showed enlarged echogenic kidneys with cysts, oligohydramnios/anhydramnios and growth malformations such as a narrow thorax and dolichocephaly. The case resulted in fetal death. The fetus was found to be homozygous for the novel TMEM67 mutation c. 457T>G (p.C153G). The mutation was predicted to be disease causing and occurred at a highly conserved residue. In another consanguineous family, antenatal ultrasound of the proband found enlarged cystic kidneys, oligohydramnios/anhydramnios, cerebellar vermis aplasia, hydrocephalus, congenital heart malformation and pericardial effusion. This case also resulted in fetal death. The proband had two similarly affected siblings and was homozygous for the novel TMEM67 splice site mutation c.1413-2A>G. This mutation also occurred at a highly conserved residue and was predicted to result in a broken acceptor site.