Joubert Syndrome 7

A number sign (#) is used with this entry because Joubert syndrome-7 (JBTS7) is caused by homozygous or compound heterozygous mutation in the RPGRIP1L gene (610937) on chromosome 16q12.

For general discussion of Joubert syndrome, see 213300.

See also Meckel syndrome type 5 (MKS5; 611561), an allelic disorder with a more severe phenotype.

Clinical Features

Delous et al. (2007) reported 4 patients from 3 French families with Joubert syndrome and renal disease. Clinical features included the molar tooth sign on brain MRI, oculomotor apraxia, ptosis, nystagmus, cerebellar ataxia, and nephronophthisis. All children except 1 had mental retardation. All developed end-stage renal disease by age 10 years, except 1 patient who developed it at 18 years. Three patients had scoliosis, and 1 had genu valgum.

Arts et al. (2007) reported 4 patients with JBTS7. Two were born of unrelated consanguineous Turkish families, and the other 2 were sibs born of unrelated European parents. The phenotype in all included the molar tooth sign, hypotonia, ataxia, developmental delay, and abnormal eye movements. One child had renal disease, and none had retinal disease. The 2 sibs had postaxial polydactyly, and 1 of them also had a small occipital encephalocele.

Brancati et al. (2008) identified homozygous mutations in the RPGRIP1L gene in 2 (12%) of 16 families with the cerebello-renal type of Joubert syndrome. No pathogenic changes in this gene were found in 118 additional patients with other Joubert syndrome phenotypes, suggesting that RPGRIP1L mutations are more common in those with the cerebello-renal subgroup, although they overall represent a rare cause of Joubert syndrome (less than 2%). In the first family, a brother and sister presented with developmental delay, growth and mental retardation, nephronophthisis, and severe scoliosis. Visual acuity, fundus examination, and liver function were normal. There was clinical variability between the 2 sibs regarding some features, with the sister being more severely affected. She died at age 17.5 years from renal failure, while he was still alive at age 22 years after kidney transplant. Both had the molar tooth sign on MRI. Molecular analysis identified a homozygous mutation in the RPGRIP1L gene (610937.0002). The second proband was a Moroccan girl who was born of consanguineous parents and presented at birth with occipital meningoencephalocele, bilateral post-axial polydactyly of hands and feet, clubfoot, and right-sided inguinal hernia. She had several episodes of hyperpnea and apnea, and delayed milestones. At age 1 year, she developed renal dysfunction associated with small kidneys with increased echogenicity, loss of corticomedullary differentiation, and multiple cysts compatible with nephronophthisis. Ocular examination showed horizontal nystagmus and alternating internal strabismus, although funduscopy was negative. At age 4 years, she has chronic renal failure, marked growth retardation and severe psychomotor delay, with lack of head control and inability to speak any meaningful word. The molar tooth sign was present on MRI. Molecular analysis identified a homozygous 1-bp deletion in the RPGRIP1L gene (610937.0010).

Mapping

By genomewide linkage and haplotype analysis, Delous et al. (2007) identified a candidate disease locus on chromosome 16q in 2 families with Joubert syndrome and renal disease.

Molecular Genetics

In French patients with Joubert syndrome and renal disease, Delous et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0001-610937.0004).

In patients with Joubert syndrome, Arts et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0008-610937.0009).