Skeletal dysplasiaGene: COPB2
Loss-of-function variants in COPB2, a component of the COPI coatomer complex, reported in six individuals from five unrelated families. 4 are heterozygous (three demonstrated de novo) and one family with two sibs with homozygous variant, previously reported but reassessed for bone phenotype. All presenting with a clinical spectrum of osteoporosis or osteopaenia, many with recurrent fractures, and developmental delay of variable severity. Functional data.
We have also added to our ID panel.
Created: 13 Sep 2021, 7:52 a.m. | Last Modified: 13 Sep 2021, 7:52 a.m.
Panel Version: 2.23
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Osteoporosis, recurrent fractures and developmental delay
Comment on list classification: Gene copied from the Osteogenesis imperfecta panel. Leaving as amber for now, but there are 2 cases with fractures and 4 with osteopaenia, plus a mouse model with low bone mass, so sufficient to rate green after then next GMS review.
Created: 24 Sep 2021, 3:32 p.m. | Last Modified: 24 Sep 2021, 3:32 p.m.
Panel Version: 2.121
Comment on mode of inheritance: Left as monoallelic for now as only 1 biallelic case reported.
Created: 16 Sep 2021, 10:45 a.m. | Last Modified: 16 Sep 2021, 10:45 a.m.
Panel Version: 2.33
As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2 +/-mice exhibit low bone mass.
PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Created: 15 Sep 2021, 4:40 p.m. | Last Modified: 15 Sep 2021, 5:08 p.m.
Panel Version: 2.29
Following discussion in the GMS musculoskeletal specialist test group Webex on 2019-06-04 it was decided to rate this gene amber until there is more evidence for an association.
Created: 11 Jun 2019, 2:59 p.m.
This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: COPB2; Suggested initial gene rating: amber
Created: 3 Apr 2019, 4:08 p.m.
In OMIM this gene is only provisionally associated with ?Microcephaly 19, primary, autosomal recessive.
The Marom et al 2018 ASBMR (American Society for Bone and Mineral Research) abstract is only accessible to society members, so no information available about how many cases reported or by what means the variants were discovered. http://www.asbmr.org/education/2018-abstracts
PubMed search does not find any other relevant publications.
Created: 2 Apr 2019, 10:41 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Request from Dr Meena Balasubramian - plausible to cause bone fragility, add to panel if possible
Created: 3 Apr 2019, 4:14 p.m.
New gene. One report linking to juvenile osteoporosis
Sources: Expert list
Created: 25 Jan 2019, 11:47 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: copb2 has been classified as Amber List (Moderate Evidence).
gene: COPB2 was added gene: COPB2 was added to Skeletal dysplasia. Sources: NHS GMS,Expert list,Expert Review Amber Q3_21_rating, watchlist_moi tags were added to gene: COPB2. Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: COPB2 were set to 34450031; 29036432 Phenotypes for gene: COPB2 were set to juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures