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Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 PTCH1 Eleanor Williams Tag for-review was removed from gene: PTCH1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 PTCH1 Eleanor Williams commented on gene: PTCH1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.62 PTCH1 Eleanor Williams Source Expert Review Green was added to PTCH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 PTCH1 Eleanor Williams commented on gene: PTCH1: This gene should be discussed as to gene rating/phenotypic scope of this panel at the next GMS review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PTCH1 Helen Lord reviewed gene: PTCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: metopic synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Tag for-review tag was added to gene: PTCH1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Classified gene: PTCH1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green review following evidence provided by expert reviewer.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Gene: ptch1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 PTCH1 Andrew Wilkie gene: PTCH1 was added
gene: PTCH1 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTCH1 were set to 31578813
Phenotypes for gene: PTCH1 were set to metopic craniosynostosis
Penetrance for gene: PTCH1 were set to Incomplete
Review for gene: PTCH1 was set to GREEN
Added comment: Several lines of evidence support that heterozygous loss-of-function mutations in PTCH1, which cause the classical genetic disorder Gorlin (basal cell naevus) syndrome, rarely also cause metopic synostosis. It is especially important to recognise this association, given the implications for patient management from a diagnosis of Gorlin syndrome.
(1) Beltrami et al (see PMID 31578813) described a frameshift variant in PTCH1 in a child with metopic synostosis.
(2) At the ESHG conference 2020, Di Giovanni et al reported 2 cases of apparently isolated trigonocephaly found to have nonsense or frameshift varaints in PTCH1. The abstract is available on weblink: https://www.abstractsonline.com/pp8/#!/9102/presentation/1801.
(3) Deletions of 9q22.3 including PTCH1 are well recognised to be associated with metopic synostosis (reviewed Yamada PMID:32028043), although genes additional to PTCH1 are included in the deleted region.
(4) In the 100kGP, the submitter is aware of a case that was missed by GEL/GMC pipeline (found by research lab) because PTCH1 was not included in the Panel for craniosynostosis.
(5) The consequence of PTCH1 loss-of-function mutations is to increase hedgehog (Hh) signalling through de-repression of Smoothened. Mutations in other genes associated with Hh overactivity, in the genes SMO, RAB23 and MEGF8, are all associated with craniosynostosis and are green panel app genes. A mice mutated in the Ptch1 orthologue, dogface-like, has lambdoid craniosynostosis (PMID:23897749). Hence, a clear biological mechanism exists accounting for craniosynostosis.
Sources: Expert Review