Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome

• Published in: Clinical neurology and neurosurgery Vol. 224; p. 107560
• Main Authors: Aksu Uzunhan, Tuğçe, Ertürk, Biray, Aydın, Kürşad, Ayaz, Akif, Altunoğlu, Umut, Yarar, Murat Hakkı, Gezdirici, Alper, İçağasıoğlu, Dilara Füsun, Gökpınar İli, Ezgi, Uyanık, Bülent, Eser, Metin, Kutbay, Yaşar Bekir, Topçu, Yasemin, Kılıç, Betül, Bektaş, Gonca, Arduç Akçay, Ayfer, Ekici, Barış, Chousein, Amet, Avcı, Şahin, Yüksel, Atıl, Kayserili, Hülya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-01-2023; Elsevier Limited
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Antigens, Neoplasm; ARMC9; Brain; Cell Cycle Proteins - genetics; Cerebellum - abnormalities; Ciliopathies - diagnosis; Ciliopathies - genetics; Ciliopathies - pathology; Cognitive ability; Congenital defects; Cytoskeletal Proteins - genetics; Eye Abnormalities - diagnosis; Eye Abnormalities - genetics; Genes; Genotype & phenotype; Hindbrain; Humans; HYLS1; Hypertension; Joubert syndrome; KATNIP; Kidney diseases; Kidney Diseases, Cystic - diagnosis; Kidney Diseases, Cystic - genetics; Liver diseases; Molar tooth sign; Mutation; Nephronophthisis; Neurodevelopmental disorders; Neurology; Optic nerve; Patients; Phenotypes; Polycystic kidney; Proteins - genetics; Retina - pathology; Retrospective Studies; Sepsis; Signs; Teeth; Istanbul Turkey; Turkey; ARMC9; KATNIP; HYLS1; Joubert syndrome; Molar tooth sign
• ISSN: 0303-8467; 1872-6968
• DOI: 10.1016/j.clineuro.2022.107560

Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement.
We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes.
The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber’s congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene.
Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.
•Joubert syndrome is classically characterized by molar tooth sign, hypotonia, and nystagmus.•Phenotypic and genetic heterogeneity is evident as there are more than 40 genes associated with the syndrome.•HYLS1 gene commonly causing hydrolethalus syndrome 1 has been associated with Joubert syndrome in our report.•Pathogenic variants in the KATNIP gene may lead to hypophyseal hormone deficiencies with mild hindbrain malformations.