Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: PRRX1

Green List (high evidence)

Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford) and reported in PMID:37154149, there is sufficient evidence for this gene to be promoted to GREEN at the next GMS update.

Created: 11 May 2023, 10:43 a.m. | Last Modified: 11 May 2023, 10:43 a.m.

Panel Version: 4.47

PMID:37154149 reported 15 patients from 12 unrelated families presenting with craniosynostosis and were identified with heterozygous variants in PRRX1 gene, while three cases from three additional families had deletion (family 13: 61.5kb; family 14: 76kb; family 15: 10.5Mb deletion). These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation.

Created: 11 May 2023, 10:41 a.m. | Last Modified: 11 May 2023, 10:41 a.m.

Panel Version: 4.44

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Agnathia-otocephaly complex, OMIM:202650; craniosynostosis, MONDO:0015469

Publications

• 36980886
• 37154149

Green List (high evidence)

There are 17 individuals from 14 unrelated families which were found to harbour rare missense substitutions of the homeodomain or loss-of-function variants. These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. Analyses were supported by immunofluorescence experiments which showed abnormal nuclear localisation of missense variants identified within the homeodomain. This work was presented as an oral presentation at the European Society of Human Genetics conference 2022 and published in a recent article by Tooze et al., 2023 (doi:10.3390/genes14030615).

Created: 2 Mar 2023, 11:56 a.m. | Last Modified: 2 Mar 2023, 11:56 a.m.

Panel Version: 3.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• https://doi.org/10.3390/genes14030615

I don't know

Unpublished work by AW found relatively common cause of mutations compared to many green genes, currently aware of 8 unrelated unpublished cases with CSS, 1 de novo and 7 inherited from unaffected parent (AW). Similar variants seen in agnathia-otocephaly phenotype (TL). ; Review on behalf of Tracy Lester and Andrew Wilkie

Created: 5 Mar 2019, 11:33 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
craniosynostosis, various combinations of sutures

Green List (high evidence)

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

Created: 11 Oct 2023, 11:55 a.m. | Last Modified: 11 Oct 2023, 11:55 a.m.

Panel Version: 4.174

Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. The group decided to rate Amber due to several unpublished cases.

Created: 21 May 2019, 4:10 p.m.

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: PRRX1; Suggested initial gene rating: amber

Created: 5 Mar 2019, 11:21 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

Our unpublished work has identified PRRX1 mutations in 6 unrelated individuals/families. Mutations are either heterozygous lof or missense changes in highly conserved homeodomain. Only one of the six mutations is de novo, remainder inherited from often clinically minimally affected parent. Note very marked contrast between these findings and previous reports of a similar spectrum of mutations causing agnathia-otocephaly; the reasons underlying this discrepancy remain unclear.

Created: 18 Oct 2017, 9:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
craniosynostosis, various combinations of sutures