Skeletal dysplasia

Gene: UNC45A

Green List (high evidence)

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

Created: 6 Mar 2022, 6:30 p.m. | Last Modified: 6 Mar 2022, 6:30 p.m.

Panel Version: 2.184

Copied this gene from the Osteogenesis imperfecta panel, as all green genes on that panel should also be green on the Skeletal dysplasia panel

Created: 25 Sep 2021, 1:43 p.m. | Last Modified: 25 Sep 2021, 1:43 p.m.

Panel Version: 2.126

Comment on list classification: Promoting this gene from grey to amber, with recommendation for green rating following GMS review. 2 unrelated families with bone fragility and biallelic variants in this gene reported in the literature, plus another case reported by an NHS laboratory.

Created: 18 Aug 2021, 3:43 p.m. | Last Modified: 18 Aug 2021, 3:43 p.m.

Panel Version: 2.19

Associated with Osteootohepatoenteric syndrome #619377 (AR) in OMIM.

As expert reviewers note, PMID: 29429573 (Esteve et al 2018) report 4 individuals from 3 families with compound het missense and nonsense variants in UNC45A. In 2 of the families bone fragility is reported as part of the phenotype. Patient lymphoblastoid cells showed a 70-93% decrease in abundance in UNC45A protein compared to controls.

Additional case with bone fragility/osteopenia reported by Julia Baptista brings the number of cases with this phenotype to three.

Created: 18 Aug 2021, 3:42 p.m. | Last Modified: 18 Aug 2021, 3:42 p.m.

Panel Version: 2.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Osteootohepatoenteric syndrome, OMIM:619377

Publications

• 29429573

Green List (high evidence)

In addition to the three families reported by Esteve et al 2018, we are aware of two additional patients with biallelic UNC45A variants. Only one had bone fragility/osteopenia, but both presented with cholestasis and diarrhoea (in one case this was congenital whereas in the other it developed early in life).

Created: 19 Feb 2021, 6:07 p.m. | Last Modified: 19 Feb 2021, 6:07 p.m.

Panel Version: 2.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
cholestasis; diarrhea; bone fragility

Publications

• 29429573

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Bone fragility is present in 3 cases from two families and is not present in another case with biallelic variants. In vitro functional assays suggest loss-of-function mechanism of disease. In vivo zebrafish assays demonstrate defects in gut development and bone fragility doesn't appear to be assessed. Emerging gene-disease association, uncertain if bone fragility is a consistent/prominent feature of the phenotype yet.
Sources: Expert list

Created: 27 Jul 2020, 12:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
cholestasis; congenital diarrhea; impaired hearing; bone fragility

Publications

• 29429573