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Fetal anomalies

Gene: SUFU

Amber List (moderate evidence)

SUFU (SUFU negative regulator of hedgehog signaling)
EnsemblGeneIds (GRCh38): ENSG00000107882
EnsemblGeneIds (GRCh37): ENSG00000107882
OMIM: 607035, Gene2Phenotype
SUFU is in 18 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

SUFU was reassessed in line with the recent expert review by Rhiannon Mellis (GOSH). The patients described by Schroder et al 2020 (PMID: 33024317) display cerebellar abnormalities that were said to be within the milder range of the Joubert clinical spectrum. However, it is unclear whether these features may conceivably be detected prenatally and therefore this gene will be flagged for review by the GMS team with regards to phenotypic fit for this panel (added 'for-review' tag).

Note that unlike the 2 Joubert syndrome families with biallelic variants reported by De Mori et al. (2017, PMID: 28965847), these individuals harboured heterozygous truncating variants in the SUFU gene. Monoallelic variants have previously been associated with basal cell nevus syndrome and medulloblastoma, and there was no evidence of tumours in any of the families described by Schroder et al.
Created: 2 Feb 2021, 11:25 a.m. | Last Modified: 2 Feb 2021, 11:40 a.m.
Panel Version: 1.612

Rhiannon Mellis (Great Ormond Street Hospital)

Green List (high evidence)

Schroder et al 2020 found SUFU heterozygous truncating variants in 15 individuals from 6 unrelated families with congenital ocular motor apraxia. These individuals did not have full-blown molar tooth sign but did have milder cerebellar abnormalities in all cases where MRI data was available: e.g. thickened and elongated cerebellar peduncles, vermis folia dysplasia and upper vermis split. Other features in these individuals were OMA +/- early onset ataxia and mild learning disability.

The authors suggest that these cases represent a milder phenotype within the Joubert clinical spectrum.

Not sure whether this is in itself sufficient evidence to promote to Green, but also found a mouse model where SUFU knockout mice displayed severely abnormal cerebellar morphology. (PMID: 21289193)
Created: 28 Jan 2021, 2:20 p.m. | Last Modified: 28 Jan 2021, 2:20 p.m.
Panel Version: 1.187

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Joubert syndrome 32

Publications

Rebecca Foulger (Genomics England curator)

I don't know

Comment when marking as ready: Marked SUFU as Ready on April 30th 2019: Fetally-relevant phenotype but currently insufficient evidence for inclusion.
Created: 30 Apr 2019, 9:42 a.m.
Comment on list classification: Kept rating as Amber awaiting further published or clinical evidence. Joubert syndrome is fetally-relevant (see review by Dierdre Cilliers) but currently only 2 unrelated cases from one paper (PMID:28965847) and SUFU is Amber on the related 'Rare multisystem ciliopathy disorders' panel (for Joubert syndrome).
Created: 24 Apr 2019, 8:35 p.m.
In 4 children from 2 unrelated consanguineous families (Egyptian and Italian) with Joubert syndrome-32 (JBTS32; 617757), De Mori et al. (2017, PMID:28965847) identified 2 different homozygous missense mutations in the SUFU gene.
Created: 11 Feb 2019, 4:14 p.m.
Comment on mode of inheritance: Changed MOI from 'both biallelic and monoallelic' to biallelic based on comment by Deirdre Cilliers: Joubert syndrome 32 (MIM:617757) has biallelic inheritance, and Basal cell nevus syndrome (MIM:109400) has monoallelic inheritance.
Created: 11 Feb 2019, 4:14 p.m.
Communication from Deirdre Cilliers, Oxford University Hospitals (via email, February 2019): Yes [SUFU should be on the Fetal anomalies panel]. Joubert syndrome would present prenatally with the cerebellar vermis hypoplasia and/or polydactyly. If the test incidentally identifies the predisposition to cancer, screening would be offered early in childhood in any case, although this would be difficult news to hear in the prenatal setting.
Created: 11 Feb 2019, 4:08 p.m.
Comment on phenotypes: Removed 'Medulloblastoma' phenotype: Although this was listed in the 'Additional genes list', this phenotype beongs on the Gene2Phenotype cancer list and not the DD list.
Created: 10 Dec 2018, 9:34 p.m.
'watchlist' tag added to highlight different DD-G2P ratings for this gene.
Created: 8 Nov 2018, 9 p.m.
In the original PAGE file: rated as Probable with biallelic inheritance for 'Joubert Syndrome with Cranio-facial and Skeletal Defects', and rated as Confirmed with monoallelic inheritance in the Additional gene list. In the original PAGE files, MOP listed as LOF in the Additional gene list, and listed as All missense/in frame for Joubert Syndrome with Cranio-facial and Skeletal Defects.
Created: 8 Nov 2018, 4:46 p.m.

History Filter Activity

2 Feb 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: SUFU.

2 Feb 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: SUFU were changed from Joubert Syndrome with Cranio-facial and Skeletal Defects; Basal cell nevus syndrome 109400 to Joubert syndrome 32, OMIM: 617757; Joubert Syndrome with Cranio-facial and Skeletal Defects

2 Feb 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: SUFU were set to 28965847

2 Feb 2021, 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 BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

30 Apr 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

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

24 Apr 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

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

11 Feb 2019, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: SUFU was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

11 Feb 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SUFU were set to

10 Dec 2018, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SUFU were changed from Medulloblastoma, desmoplastic 155255; Joubert Syndrome with Cranio-facial and Skeletal Defects; Basal cell nevus syndrome 109400 to Joubert Syndrome with Cranio-facial and Skeletal Defects; Basal cell nevus syndrome 109400

8 Nov 2018, Gel status: 2

Added Tag

Rebecca Foulger (Genomics England curator)

Tag watchlist tag was added to gene: SUFU.

8 Nov 2018, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Added phenotypes Medulloblastoma, desmoplastic 155255 for gene: SUFU

8 Nov 2018, Gel status: 2

Added New Source, Set Phenotypes

Rebecca Foulger (Genomics England curator)

Source PAGE Additional Gene List was added to SUFU. Added phenotypes Basal cell nevus syndrome 109400 for gene: SUFU

8 Nov 2018, Gel status: 2

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

Rebecca Foulger (Genomics England curator)

gene: SUFU was added gene: SUFU was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber Mode of inheritance for gene: SUFU was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: SUFU were set to Joubert Syndrome with Cranio-facial and Skeletal Defects