Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: PTCH1

I don't know

Giovanni et al abstract - two cases both had isolated trigonocephaly.
Beltrami et al paper the patient presented with phenotype similar to 9q22.3 microdeletion syndrome (includes the PTCH1 gene) but shown to have a fs variant in PTCH1. This patient presented with craniosynostosis of all sutures. Of note patients with isolated metopic synostosis would not be tested on this panel as it is for multisuture/complex craniosynostosis.

Created: 22 Jan 2021, 1:34 p.m. | Last Modified: 22 Jan 2021, 1:34 p.m.

Panel Version: 2.19

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
metopic synostosis

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 5 Mar 2022, 5:41 p.m. | Last Modified: 5 Mar 2022, 5:41 p.m.

Panel Version: 2.63

This gene should be discussed as to gene rating/phenotypic scope of this panel at the next GMS review.

Created: 26 Jan 2021, 5:11 p.m. | Last Modified: 26 Jan 2021, 5:11 p.m.

Panel Version: 2.22

Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green review following evidence provided by expert reviewer.

Created: 21 Jan 2021, 5:10 p.m. | Last Modified: 21 Jan 2021, 5:10 p.m.

Panel Version: 2.18

Green List (high evidence)

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

Created: 19 Jan 2021, 12:01 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
metopic craniosynostosis

Publications

• 31578813