Joubert syndrome and other neurological ciliopathies

Gene: SUFU

Green List (high evidence)

Heterozygous truncating variants in SUFU in 15 subjects from 6 unrelated families of various ethnic backgrounds (familial and de novo cases). Clinical features of early-onset (congenital) ocular ataxia and developmental delay, with some phenotypic variability. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign of Joubert syndrome. Paper reports that condition reported here and SUFU-associated Basal cell nevus syndrome (Gorlin) are likely allelic disorders, as there is currently no convincing evidence for a clinical overlap.

Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Knockout mice with SuFu deficiency demonstrated that SuFu is required for proper midhindbrain patterning and controls cerebellar patterning.

Created: 8 Feb 2021, 1:53 a.m. | Last Modified: 8 Feb 2021, 1:53 a.m.

Panel Version: 0.92

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenital ocular motor apraxia (forme fruste of Joubert syndrome)

Publications

• PMID: 33024317

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Further 22 individuals reported with LoF variants in SUFU and a phenotype described as being on the mild end of JS.
Clinical features included congenital oculomotor apraxia, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles.

Created: 9 Mar 2022, 2:45 a.m. | Last Modified: 9 Mar 2022, 2:45 a.m.

Panel Version: 1.17

Two unrelated families described with what are postulated to be hypomorphic bi-allelic variants in this gene and Joubert syndrome. Note gene also causes dominant Basal Cell Nevus Syndrome.

Created: 29 Feb 2020, 6:11 a.m. | Last Modified: 29 Feb 2020, 6:11 a.m.

Panel Version: 0.16

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
SUFU-related neurodevelopmental disorder, Joubert-like; Joubert syndrome 32, MIM# 617757

Publications

• 34675124