Osteogenesis imperfecta

Gene: MBTPS2

I don't know

As per EW review; only 2 families reported by Lindert et al 2016, cannot find any other cases in the literature.
Evidence that variants cause cleavage or activation of S2P substrates OASIS and ATF6, respectively, to be impaired.

More recently, Lim et al (2021) provide a possible explanation as to why the two missense variants identified by Lindert et al (2016) cause OI rather than the dermatological conditions caused by other nearby missense variants. RNA-sequencing-based transcriptome profiling was used to identify genes that are differentially expressed between the OI causing variants and two dermatological (IFAP/KFSD) variants. Not sure the evidence is strong enough to class as green.

Created: 17 Jan 2022, 4:52 p.m. | Last Modified: 17 Jan 2022, 4:52 p.m.

Panel Version: 2.37

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
OI type XIX OMIM301014

Publications

• PMID: 34093655

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. It has been agreed that this gene should remain amber at this time.

Created: 5 Mar 2022, 9:33 p.m. | Last Modified: 5 Mar 2022, 9:33 p.m.

Panel Version: 2.43

Comment on list classification: Promoting from grey to amber. Only 2 cases reported in literature so waiting for further GMS feedback on the rating of this gene.

Created: 15 Sep 2021, 1:24 p.m. | Last Modified: 15 Sep 2021, 1:24 p.m.

Panel Version: 2.25

Associated with Osteogenesis imperfecta, type XIX #301014 (AR) in OMIM.

PMID: 27380894 - Lindert et al 2016 - report two independent OI pedigrees (Thai and German) without symptoms of any dermatological condition previously associated with variants in this gene(ichthyosis follicularis, atrichia, and photophobia (IFAP); BRESEK/BRESHECK syndrome; and keratosis follicularis spinulosa decalvans (KFSD)). In both families missense mutations were identified which was in or near the S2P NPDG motif vital for metal ion coordination. All those affected were male. Mutant S2P protein was found to be stable but cleavage or activation of S2P substrates OASIS and ATF6, respectively, was impaired, consistent with reduced proband collagen secretion.

A search of PubMed finds no further cases.

Created: 15 Sep 2021, 1:05 p.m. | Last Modified: 15 Sep 2021, 1:18 p.m.

Panel Version: 2.24

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Osteogenesis imperfecta, type XIX, OMIM:301014

Publications

• 27380894

Green List (high evidence)

Well established gene in OI first published in 2016 and more cases published since.

Created: 8 Sep 2021, 12:35 p.m. | Last Modified: 8 Sep 2021, 12:35 p.m.

Panel Version: 2.23

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Ostoegenesis Imperfecta; Fractures

Publications

• 27380894

I don't know

Two unrelated families reported with multiple male affected individuals.
Sources: Expert list

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

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Osteogenesis imperfecta, type XIX, MIM# 301014

Publications

• 27380894