Ophthalmological ciliopathies

Gene: SUFU

Green List (high evidence)

SUFU (SUFU negative regulator of hedgehog signaling)
EnsemblGeneIds (GRCh38): ENSG00000107882
EnsemblGeneIds (GRCh37): ENSG00000107882
OMIM: 607035, Gene2Phenotype
SUFU is in 21 panels

5 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to Green but the mode of inheritance has been set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. Additional comments from reviewing GLHs: 'Consensus view: Monoallelic and biallelic'.
Created: 10 Oct 2023, 10:19 a.m. | Last Modified: 10 Oct 2023, 10:19 a.m.
Panel Version: 3.3

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Created: 12 Dec 2022, 12:54 p.m. | Last Modified: 12 Dec 2022, 12:54 p.m.
Panel Version: 2.3
Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Created: 12 Dec 2022, 12:53 p.m. | Last Modified: 12 Dec 2022, 12:53 p.m.
Panel Version: 2.2
To date, only 2 unrelated cases with a Joubert-like phenotype 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, 12:53 p.m. | Last Modified: 12 Dec 2022, 12:53 p.m.
Panel Version: 2.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Joubert syndrome 32, OMIM:617757

Publications

Rebecca Foulger (Genomics England curator)

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.

Andrea Nemeth (University of Oxford)

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

Zornitza Stark (Australian Genomics)

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

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

History Filter Activity

10 Oct 2023, Gel status: 3

Removed Tag, Removed Tag, Removed Tag, Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag watchlist_moi was removed from gene: SUFU. Tag Q4_22_MOI was removed from gene: SUFU. Tag Q4_22_promote_green was removed from gene: SUFU. Tag Q4_22_expert_review was removed from gene: SUFU.

10 Oct 2023, Gel status: 3

Added New Source, Added New Source, Set mode of inheritance, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Green was added to SUFU. Source NHS GMS was added to SUFU. Mode of inheritance for gene SUFU was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

11 May 2023, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q4_22_expert_review tag was added to gene: SUFU.

12 Dec 2022, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: SUFU were set to 28965847

12 Dec 2022, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: sufu has been classified as Amber List (Moderate Evidence).

12 Dec 2022, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

12 Dec 2022, Gel status: 2

Added Tag, Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist_moi tag was added to gene: SUFU. Tag Q4_22_MOI tag was added to gene: SUFU. Tag Q4_22_promote_green tag was added to gene: SUFU.

8 Nov 2022, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757

11 Jul 2019, Gel status: 2

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Ivone Leong (Genomics England Curator)

gene: SUFU was added gene: SUFU was added to Ophthalmological ciliopathies. Sources: Expert list,Expert Review Amber Mode of inheritance for gene: SUFU was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUFU were set to 28965847 Phenotypes for gene: SUFU were set to Joubert syndrome 32, 617757