Skeletal dysplasia

Gene: P4HB

Green List (high evidence)

OI and decreasing bone density gp of SD - >3 cases. recurrent Y393C variant + intragenic deletion. LOF variants unknown aetiology.; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cole-Carpenter syndrome 1 112240

Publications

• 25683117
• 29384951
• 30063094

Mode of pathogenicity
Other - please provide details in the comments

I don't know

Comment on mode of pathogenicity: 1 missense variant reported to date + deletion of several exons.

Created: 21 Nov 2019, 4:40 p.m. | Last Modified: 21 Nov 2019, 4:40 p.m.

Panel Version: 1.237

Comment on list classification: Changing rating from red to green. > 3 cases.
Including OI genes on this panel.

Created: 21 Nov 2019, 4:38 p.m. | Last Modified: 21 Nov 2019, 4:38 p.m.

Panel Version: 1.236

Associated with Cole-Carpenter syndrome 1 (112240) in OMIM.

PMID: 25683117 - Rauch et al. (2015) - 2 cases. 2 unrelated male patients with Cole-Carpenter syndrome-1, who exhibited multiple fractures of the long bones as well as craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features/ Identified heterozygosity for the same missense mutation in the P4HB gene ( c.1178A-G transition, Y393C) in both patients. In one the mutation occured de novo, in the other the unaffected father was mosaic for the variant.

PMID: 29384951 - Ouyang and Yang 2017 - 1 case. A 14-month-old Chinese girl presented with prominent ocular proptosis, frontal bossing, craniosynostosis, plump anterior fontanel, growth retardation, osteopenia, and distinctive facial features. Her clinical manifestation is similar to the 2 cases previously described with Cole–Carpenter syndrome-1. Whole-exome sequencing revealed a novel heterozygous deletion variation in exons 5 to 8 of the P4HB gene, which was found to be heterozygous.

PMID: 30063094 - Porntaveetus et al 2018 - 1 case. First Asian CCS patient possessing the recurrent mutation in P4HB (c.1178A>G ).

3 cases with SNV in P4HB and Cole–Carpenter syndrome-1 - all the same missense variant. Different ethnicities. One patient with several exons deleted.

Created: 8 May 2019, 2:57 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: P4HB; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment on list classification: One variant reported in two unrelated individuals

Created: 11 Jul 2016, 9:03 a.m.