Skeletal ciliopathies

Gene: SUFU

I don't know

Comment on list classification: Recessive phenotype fits the scope of this panel; however only two cases have been reported to date in a single paper. Monoallelic form does not appear to feature skeletal abnormalities but rather is dominated by neurological phenotypes. Therefore maintaining Amber rating and biallelic MOI on this panel but adding a watchlist tag.

Created: 12 Dec 2022, 2:46 p.m. | Last Modified: 12 Dec 2022, 2:46 p.m.

Panel Version: 2.3

To date, only 2 unrelated cases with a Joubert-like phenotype (including postaxial polydactyly) and hypomorphic biallelic variants have been reported (PMID: 28965847). The phenotype is listed in OMIM and G2P (strong confidence category). There is also a knockout mouse model displaying severely abnormal cerebellar morphology (PMID: 21289193). However, an Amber classification was previously selected based on the evidence and there have been no further publications of recessive disease since the initial case report.

Recently, two papers (PMID: 33024317, 34675124) were published describing 23 total families with heterozygous variants in individuals who presented a milder phenotype within the Joubert clinical spectrum. Phenotype was characterised by congenital ocular motor apraxia (COMA) in all individuals and other variable features such as DD/ID, ataxia, cerebellar and brainstem anomalies. There was a lack of conclusive retinal, kidney, liver or skeletal involvement typical of Joubert syndrome. Some variants were inherited from asymptomatic carrier parents suggesting reduced penetrance. None had evidence of cancer.

Created: 12 Dec 2022, 1:04 p.m. | Last Modified: 12 Dec 2022, 1:04 p.m.

Panel Version: 2.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Joubert syndrome 32, OMIM:617757

Publications

• 21289193
• 28965847
• 33024317
• 34675124

PMID:28965847 - De Mori et al 2017 - 4 subjects from 2 families. All subjects presented peculiar facial dysmorphisms (hypertelorism, broad and depressed nasal bridge, frontal bossing), oculomotor apraxia, developmental delay with mild intellectual impairment, gait ataxia, and dysarthria. Three of them had post-axial polydactyly and two had global macrosomia with macrocephaly. One child also showed a few small dyskeratotic pits on the foot soles

Created: 11 Jul 2019, 3:11 p.m. | Last Modified: 27 Nov 2019, 3:12 p.m.

Panel Version: 0.21

Comment on list classification: Updated rating from Grey to Amber. Probable DD-G2P gene for Joubert Syndrome. 2 unrelated families from 1 paper. Biochemical assays in the paper (PMID:28965847) show that SUFU missense variants impair GLI3 binding, but further cases and/or animal model required for diagnostic rating.

Created: 1 Nov 2018, 2:34 p.m.

Added 'watchlist' tag.

Created: 16 Oct 2018, 8:28 p.m.

As the Reviewers state, PMID:28965847 (De Mori et al., 2017) performed whole-exome sequencing in subjects with Joubert syndrome and identified 4 children from 2 unrelated families (Italian and Egyptian) carrying homozygous missense variants in SUFU; c.1217T-C, NM_016169.3, p.I406T in the Italians, and c.527A-G, NM_016169.3, p.H176R in the Egyptians. The Italian patients also carried a homozygous T716S mutation in the CDHR1 gene. Three of the children had postaxial polydactyly.

Created: 16 Oct 2018, 8:20 p.m.

Green List (high evidence)

Four mutations in two consanguineous families, causing a complex Joubert-like phenotype with dysmorphic features and a molar tooth sign. Extensive laboratory evidence also provided on the role of this gene in cilial function. The paper (28965847) is from two of the largest groups in the Joubert syndrome/ciliopathy field, so although it is only one publication I think it just makes it into the green list, but with review recommended.

Created: 16 Sep 2018, 7:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 28965847

I don't know

4 individuals from two unrelated families reported in the literature with hypomorphic bi-allelic variants in this gene and a Joubert syndrome phenotype. Probably merits Amber.

Created: 7 Aug 2018, 4:53 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Joubert Syndrome 32, MIM#617757

Publications

• 28965847

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