A number sign (#) is used with this entry because of evidence that Joubert syndrome-30 (JBTS30) is caused by homozygous or compound heterozygous mutation in the ARMC9 gene (617612) on chromosome 2q37.

For discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Van De Weghe et al. (2017) reported 11 patients from 8 unrelated families with JBTS. Most of the families were Caucasian, but 2 families were from Saudi Arabia. Most of the patients were children, although 2 sibs were adults. The patients had typical features of Joubert syndrome, including delayed development and developmental disability, most severely affecting motor and speech, as well as abnormal eye movements, often with ptosis. Additional features were more variable, including apnea and breathing abnormalities, retinal dystrophy (2 patients), postaxial polydactyly (2 patients), and seizures (2 patients). One patient (UW349-3) had a more complex phenotype with hypopituitarism, optic nerve hypoplasia, bifid uvula, and abnormal brainstem. None of the patients had documented renal or hepatic involvement. Brain imaging showed the molar tooth sign in all patients, as well as dysplasia of the superior cerebellar folia. Less common features seen in 1 or 2 patients included Dandy-Walker malformation and heterotopia.

The transmission pattern of JBTS30 in the families reported by Van De Weghe et al. (2017) was consistent with autosomal recessive inheritance.

In 11 patients from 8 unrelated families with JBTS30, Van De Weghe et al. (2017) identified 10 different homozygous or compound heterozygous mutations in the ARMC9 gene (see, e.g., 617612.0001-617612.0009). The mutations included 6 missense, 1 nonsense, 2 splice site, and 1 intragenic deletion. Mutations in the first 2 families were found by whole-exome sequencing of 53 patients from 51 families with a clinical diagnosis of Joubert syndrome in whom mutations in 28 JBTS-associated genes had been excluded. Mutations in 3 additional unrelated patients were found by targeted sequencing of the ARMC9 gene in 534 individuals from 456 families; the remaining 2 families were ascertained from a cohort of Saudi Arabian families who underwent exome sequencing. All variants were confirmed by Sanger sequencing and segregated with the disorder in all 7 families in which parental DNA was available. Several of the mutations were found at very low frequencies in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.

Van De Weghe et al. (2017) found that CRISPR/Cas9-mediated knockout of armc9 in zebrafish resulted in curved body shape, retinal dystrophy, coloboma, reduced cilia number in ventricles, and shortened cilia in photoreceptor outer segments.