Rare syndromic craniosynostosis or isolated multisuture synostosis
Gene: PRRX1
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
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
Unpublished work by AW found relatively common cause of mutations compared to many green genes, currently aware of 8 unrelated unpublished cases with CSS, 1 de novo and 7 inherited from unaffected parent (AW).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 WilkieCreated: 5 Mar 2019, 11:33 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
craniosynostosis, various combinations of sutures
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: amberCreated: 5 Mar 2019, 11:21 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Tag Q2_23_promote_green was removed from gene: PRRX1.
Source Expert Review Green was added to PRRX1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Tag Q2_23_promote_green tag was added to gene: PRRX1.
Phenotypes for gene: PRRX1 were changed from craniosynostosis, various combinations of sutures to Agnathia-otocephaly complex, OMIM:202650; craniosynostosis, MONDO:0015469; craniosynostosis, various combinations of sutures
Publications for gene: PRRX1 were set to
Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Source NHS GMS was added to PRRX1.
This proposed gene was validated and added to this panel
PRRX1 was added to Craniosynostosis syndromes phenotypespanel. Sources: Expert Review
PRRX1 was created by awilkie