#615665
Table of Contents
A number sign (#) is used with this entry because of evidence that Joubert syndrome-22 (JBTS22) is caused by homozygous mutation in the PDE6D gene (602676) on chromosome 2q37.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Thomas et al. (2014) reported a consanguineous family in which 2 sibs had Joubert syndrome. An infant girl presented with intrauterine growth retardation, facial dysmorphism, postaxial polydactyly of feet, syndactyly, renal hypoplasia, microphthalmia, and an extinguished electroretinogram. Brain MRI confirmed the diagnosis of Joubert syndrome. Her brother had polydactyly, microphthalmia, and coloboma. A third sib was a male fetus terminated at 14 weeks' gestation following the observation of brain anomalies and polydactyly. Fetal examination showed severe retinal dysplasia.
Megarbane et al. (2019) reported a male infant, born to consanguineous Lebanese parents, who was found at birth to have bilateral postaxial polydactyly on the hands and feet. On examination at 6 months of age, he had hypotonia and oculomotor apraxia. He was nondysmorphic and he did not have abnormal breathing or sleep apnea. An abdominal and pelvic ultrasound was normal. Brain MRI showed agenesis of the cerebellar vermis, a hypoplastic corpus callosum, cortical atrophy of the temporal lobes, and the molar tooth sign.
The transmission pattern of Joubert syndrome in the family reported by Thomas et al. (2014) was consistent with autosomal recessive inheritance.
In 3 sibs, born of consanguineous parents, with Joubert syndrome, Thomas et al. (2014) identified a homozygous splice site mutation in the PDE6D gene (602676.0001). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutant protein localized normally to the basal body of primary cilia in patient fibroblasts, and the morphology of cilia was normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (613037), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E trafficking and targeting. Screening the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations.
In a male infant, born to consanguineous Lebanese parents, with Joubert syndrome, Megarbane et al. (2019) identified a homozygous mutation in the PDE6D gene (602676.0002). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Thomas et al. (2014) found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers.
Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S. A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22). Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article. [PubMed: 30423442, related citations] [Full Text]
Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum. Mutat. 35: 137-146, 2014. [PubMed: 24166846, images, related citations] [Full Text]
ORPHA: 2754, 475; DO: 0110991;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.1 | Joubert syndrome 22 | 615665 | Autosomal recessive | 3 | PDE6D | 602676 |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-22 (JBTS22) is caused by homozygous mutation in the PDE6D gene (602676) on chromosome 2q37.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Thomas et al. (2014) reported a consanguineous family in which 2 sibs had Joubert syndrome. An infant girl presented with intrauterine growth retardation, facial dysmorphism, postaxial polydactyly of feet, syndactyly, renal hypoplasia, microphthalmia, and an extinguished electroretinogram. Brain MRI confirmed the diagnosis of Joubert syndrome. Her brother had polydactyly, microphthalmia, and coloboma. A third sib was a male fetus terminated at 14 weeks' gestation following the observation of brain anomalies and polydactyly. Fetal examination showed severe retinal dysplasia.
Megarbane et al. (2019) reported a male infant, born to consanguineous Lebanese parents, who was found at birth to have bilateral postaxial polydactyly on the hands and feet. On examination at 6 months of age, he had hypotonia and oculomotor apraxia. He was nondysmorphic and he did not have abnormal breathing or sleep apnea. An abdominal and pelvic ultrasound was normal. Brain MRI showed agenesis of the cerebellar vermis, a hypoplastic corpus callosum, cortical atrophy of the temporal lobes, and the molar tooth sign.
The transmission pattern of Joubert syndrome in the family reported by Thomas et al. (2014) was consistent with autosomal recessive inheritance.
In 3 sibs, born of consanguineous parents, with Joubert syndrome, Thomas et al. (2014) identified a homozygous splice site mutation in the PDE6D gene (602676.0001). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutant protein localized normally to the basal body of primary cilia in patient fibroblasts, and the morphology of cilia was normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (613037), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E trafficking and targeting. Screening the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations.
In a male infant, born to consanguineous Lebanese parents, with Joubert syndrome, Megarbane et al. (2019) identified a homozygous mutation in the PDE6D gene (602676.0002). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Thomas et al. (2014) found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers.
Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S. A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22). Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article. [PubMed: 30423442] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.010]
Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum. Mutat. 35: 137-146, 2014. [PubMed: 24166846] [Full Text: https://doi.org/10.1002/humu.22470]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM