Lagier-Tourenne et al. (2004) described 2 consanguineous families with Joubert syndrome, one Turkish and the other of Swiss origin; the latter was originally described by Boltshauser and Isler (1977). There were 5 affected members in the Turkish family ... Lagier-Tourenne et al. (2004) described 2 consanguineous families with Joubert syndrome, one Turkish and the other of Swiss origin; the latter was originally described by Boltshauser and Isler (1977). There were 5 affected members in the Turkish family and 2 in the Swiss family. All patients had early hypotonia, molar tooth sign, and cerebellar vermis hypoplasia. Other clinical features included cognitive impairment, neonatal breathing problems, cerebellar ataxia, nystagmus, retinal dystrophy, reduced vision, kyphoscoliosis, and retarded skeletal growth. In a review of patients with JBTS3, Valente et al. (2005) found that multiple central nervous system anomalies often occurred, including polymicrogyria, malformations of the corpus callosum, seizures, and spasticity. In contrast to patients with JBTS1 (see 213300), renal disease, liver disease, and polydactyly had not been reported. Utsch et al. (2006) reported 2 Pakistani brothers, born of consanguineous parents, with JBTS3. Both boys had cerebellar ataxia, developmental delay, nystagmus, oculomotor apraxia. One developed end-stage renal failure by age 16 years due to nephronophthisis. Molecular analysis identified a homozygous mutation in the AHI1 gene (608894.0007). The findings indicated that renal involvement can occur in patients with JBTS3.
Ferland et al. (2004) identified a locus associated with Joubert syndrome on 6q23.2-q23.3 and found 3 deleterious mutations in the gene encoding Abelson helper integration site-1 (AHI1; 608894.0001-608894.0003). AHI1 was found to be most highly expressed in brain, ... Ferland et al. (2004) identified a locus associated with Joubert syndrome on 6q23.2-q23.3 and found 3 deleterious mutations in the gene encoding Abelson helper integration site-1 (AHI1; 608894.0001-608894.0003). AHI1 was found to be most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicated that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors. In affected members of 3 consanguineous families with Joubert syndrome, some with cortical polymicrogyria, Dixon-Salazar et al. (2004) identified 1 missense and 2 frameshift mutations in the AHI1 gene. Using a combination of haplotype analysis and gene sequencing, Parisi et al. (2006) screened 117 probands with Joubert syndrome for mutations in the AHI1 gene and identified a total of 15 novel and 5 previously identified mutations in 19 families, including nonsense, missense, splice site, and insertion mutations. Fourteen of the mutation-positive families were consanguineous, but no single founder mutation was apparent. In addition to the molar tooth sign, retinal dystrophy was present in 12 families; however, no individuals exhibited variable signs of Joubert syndrome such as polydactyly, encephalocele, colobomas, or liver fibrosis. Valente et al. (2006) identified 15 different mutations (see, e.g., 608894.0004-608894.0006) in the AHI1 gene in 11 patients from 10 families with Joubert syndrome. These patients accounted for 7.3% of 137 probands with the molar tooth sign and Joubert-related disorders. A phenotype-specific group of Joubert syndrome plus retinopathy had an AHI1 mutation frequency was 21.7% (5 of 23 probands). Clinical analysis indicated that AHI1 mutations were not associated with kidney or liver changes. Retinal abnormalities ranged from retinitis pigmentosa to blindness. By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a nonsense and a missense mutation in the AHI1 gene in affected members of 2 families with Joubert syndrome-3 (608894.0008 and 608894.0009, respectively).