Limb disorders

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, 2:48 p.m. | Last Modified: 12 Dec 2022, 2:48 p.m.

Panel Version: 3.4

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, 2:47 p.m. | Last Modified: 12 Dec 2022, 2:47 p.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Joubert syndrome 32, OMIM:617757

Publications

• 21289193
• 28965847
• 33024317
• 34675124

I don't know

De Mori AJHG 101:552-63;2017

Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.

Panel Version: 1.24

I don't know

Comment on list classification: 3 out of 4 children from 2 families had post-axial polydactyly so rating amber. Rating agreed with Genomics England clinical team.

Created: 26 Nov 2019, 12:17 a.m. | Last Modified: 26 Nov 2019, 12:17 a.m.

Panel Version: 1.122

Associated with Joubert syndrome 32 (#617757) in OMIM and Joubert Syndrome with Cranio-facial and Skeletal Defects in Gene2Phenotype (probable).

PMID: 28965847 - Mori et al 2017 - 2 cases. They report four children from two unrelated consanguineous families (from Italy and Egypt) carrying homozygous missense variants (c.1217T>C,p.Ile406Thr and c.1218C>G,p.Ile406Met) in SUFU. The children presented with congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and 3 had postaxial polydactyly.
In family 1, the two affected siblings also had a homozygous missense variant in CDHR1 but is expressed only in the outer nuclear layer of the retina and pathogenic variants of this gene are known to cause an autosomal-recessive form of cone-rod dystrophy with onset in the late second decade of life (older than the probands).
Functional studies on fibroblasts and cell lines showed that the mutant proteins were less stable and more rapidly degraded than SUFU WT and had impaired ability to bind GLI3 and promote its cleavage into the repressor form GLI3R, while they maintained unaltered ability to bind GLI1. These findings suggest that both variants are hypomorphic alleles, resulting only in a partial loss of the normal gene function.

Created: 7 Aug 2019, 10:16 a.m. | Last Modified: 7 Aug 2019, 10:16 a.m.

Panel Version: 1.39

Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list

Created: 1 Aug 2019, 4:24 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal