A number sign (#) is used with this entry because of evidence that Joubert syndrome-37 (JBTS37) is caused by homozygous or compound heterozygous mutation in the TOGARAM1 gene (617618) on chromosome 14q21.

Joubert syndrome-37 (JBTS37) is an autosomal recessive neurodevelopmental ciliopathy characterized classically by a distinctive hindbrain malformation affecting the midbrain and cerebellum, recognizable as the 'molar tooth sign' on brain imaging. Affected individuals have hypotonia, ataxia, and variably impaired intellectual development. Additional variable features, such as postaxial polydactyly, liver or kidney anomalies, retinal dystrophy, and coloboma, may also occur. In severe cases, affected fetuses with these malformations may be terminated (summary by Latour et al., 2020).

For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Latour et al. (2020) reported 5 unrelated patients, including a fetus, with clinical features consistent with Joubert syndrome, including neurodevelopmental delay and classic brain imaging findings of absent cerebellar vermis and thick, horizontally oriented superior cerebellar peduncles, giving the appearance of the molar tooth sign. The fetus had cerebellar vermis hypoplasia, postaxial foot polydactyly, and abnormal craniofacial features, such as broad nasal bridge and posteriorly rotated ears. The living children, who ranged from 6 to 16 years of age, had hypotonia, ataxia, cognitive impairment, poor or absent speech, and behavioral abnormalities. More variable features included abnormal eye movements, apnea, kidney and liver involvement, and postaxial polydactyly. One patient (WGL-1914) had hydronephrosis, hepatomegaly, cholestasis, microphthalmia, and coloboma, and another (JAS-L50) had a small scarred left kidney and short stature. Dysmorphic features included broad nasal bridge or nose with anteverted alae, deep-set eyes, hypertelorism, metopic ridge, frontal bossing, low-set ears, ptosis, high-arched palate, widely-spaced nipples, small scrotum, micropenis, undescended testes, hyperlordosis, and joint hypermobility. The patients were ascertained from several large cohorts of patients with clinical features of JBTS, a ciliopathy, or neurodevelopmental disorders who underwent exome or genome sequencing.

Morbidoni et al. (2021) reported a family in which 2 male fetuses, born of unrelated parents, were terminated in the second trimester due to multiple fetal abnormalities. The fetuses had microcephaly, microphthalmia, cleft lip and palate, and brain malformations. Both had hydrocephalus, 1 had cerebellar hypoplasia, and the other had lissencephaly. The heart and skeletal systems were normal; renal and hepatic features were not mentioned. The authors noted phenotypic overlap with Meckel-Gruber syndrome (see MKS1, 249000).

The transmission pattern of JBTS37 in the families reported by Latour et al. (2020) was consistent with autosomal recessive inheritance.

In 5 unrelated patients, including a fetus, with JBTS37, Latour et al. (2020) identified homozygous or compound heterozygous mutations in the TOGARAM1 gene (see, e.g., 617618.0001-617618.0006). The mutations, which were found by exome sequencing of several large cohorts of patients with JBTS, segregated with the disorder in the families and were either very rare or not present in the gnomAD database. There were missense and nonsense mutations, as well as an intragenic deletion, and most mutations affected the TOG2 and TOG3 functional domains of the protein. In vitro functional cellular expression studies of some of the variants in TOGARAM1-null retinal pigment epithelial (RPE) cells showed that those affecting the TOG2 domain (R368W, 617618.0005 and L375P, 617618.0001), which promotes microtubule polymerization, resulted in longer cilia compared to controls, whereas a mutation affecting the TOG3 domain (R1311C; 617618.0002) resulted in shortened cilia. Variants in the TOG2 domain abolished the interaction between TOGARAM1 and ARMC9 (617612), whereas the TOG3 mutation did not influence this interaction. Fibroblasts, available from 1 patient (UW360-3) only, showed slightly shorter cilia length compared to controls (2.6 versus 3.0 micrometers) and a slightly lower ciliation rate compared to controls (85% versus 91%). Further detailed studies of patient fibroblasts and ciliated cells from mutant zebrafish showed reduced acetylation and polyglutamylation of axonemal microtubules compared to controls, indicating impaired posttranslational modification of tubulin, as well as abnormal ciliary stability. There was also evidence of impaired SHH (600725)/ SMO (601500) signaling. The transition zone (TZ), which connects the axoneme to the ciliary membrane, was unaffected. Latour et al. (2020) initially used ARMC9 as a bait to identify interacting proteins, which yielded TOGARAM1 as a candidate gene for Joubert syndrome. The findings characterized a novel ARMC9/TOGARAM1 protein module that plays an important role in ciliary stability and function.

In 2 male fetuses, born of unrelated parents, with a severe form of JBTS37, Morbidoni et al. (2021) identified compound heterozygous mutations in the TOGARAM1 gene (R368W, 617618.0005 and R1207X, 617618.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Morbidoni et al. (2021) noted that knockdown of the C. elegans orthologous TOGARAM1 gene (che12) results in ciliary defects. Che12 is expressed in ciliated dendritic sensory neurons. Generation of mutant C. elegans harboring a R284W mutation (equivalent to the human R368W mutation) demonstrated normal chemotaxis, but had defective uptake of lipophilic dye compared to controls. This was associated with shortened cilium length and disorganized ciliary architecture. Expression of the corresponding mouse mutation (R367W) in E. coli resulted in increased tubulin polymerization, suggesting altered tubulin-binding activity of mutant Togaram1. These findings were consistent with a hypomorphic effect of the missense variant.

Using Cas9-triggered homologous recombination, Das et al. (2015) generated a C. elegans mutant with a deletion of the coding sequence of Che12, the C. elegans Crescerin-1 ortholog. C. elegans with the Che12 deletion displayed dramatically shorter cilia compared with wildtype. Cilia of Che12 deletion mutants also exhibited ultrastructural defects, including poorly defined microtubule architecture, and they were unable to sense and respond to a sodium chloride gradient in chemotaxis assays. In strains with targeted mutations of Che12 TOG domains, mutant Che12 properly localized to cilia, but the mutants otherwise phenocopied the Che12 deletion strain. Das et al. (2015) concluded that the TOG domain tubulin-binding activity of Che12 is required for proper sensory cilia development and cilia-based chemotactic function in C. elegans.

Latour et al. (2020) found that knockdown of the togaram1 ortholog in zebrafish resulted in increased frequency of ciliary defects, including curved body shape with scoliosis and development of kidney cysts. The phenotype resembled that of zebrafish with mutant armc9 (617612). Both mutant animals had reduced numbers of shortened pronephric, ventricular, and nose pit cilia.