Osteogenesis imperfecta

Gene: SGMS2

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The reviewers note that the associated phenotype appears variable, and that R104 Skeletal Dysplasia panel looks a better fit for this gene.

Created: 2 Feb 2023, 11:26 p.m. | Last Modified: 2 Feb 2023, 11:26 p.m.

Panel Version: 3.5

Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 8 cases reported with 3 different variants.

Created: 16 Sep 2021, 11:53 a.m. | Last Modified: 16 Sep 2021, 11:53 a.m.

Panel Version: 2.35

PMID:30779713 - Pekkinen et al 2019 - report 4 unrelated families (Finland, USA, that share the same heterozygous nonsense variant, c.148C>T (p.Arg50*) in SGMS2, who presented with childhood-onset osteoporosis with or without cranial sclerosis. They also report two families (Dutch and Hispanic) with heterozygous missense variants, c.185T>G (p.Ile62Ser) or c.191T>G (p.Met64Arg) in SGMS2 who had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasia. The p.Arg50* mutation resulted in a catalytically inactive enzyme. The p.Ile62Ser and p.Met64Arg variants enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum.


PMID: 32028018 - Robinson et al 2020 - report 2 additional unrelated patients in which the SGMS2 p.Arg50* variant in was identified. Both had childhood-onset osteoporosis. In family 1, the variant was de novo. In family 2 the variant was inherited from the father (history of chronic back pain and cardiac arrhythmia but did not have a history of a low-trauma long-bone fracture.) They found that the p.Arg50* variant was associated with phenotypic variability, ranging from absence of a bone phenotype to severe vertebral compression fractures and low lumbar spine areal bone mineral density.

Created: 16 Sep 2021, 11:51 a.m. | Last Modified: 16 Sep 2021, 11:51 a.m.

Panel Version: 2.33

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia, OMIM:126550; calvarial doughnut lesions-bone fragility syndrome, MONDO:0007470

Publications

• 30779713
• 32028018

Green List (high evidence)

12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments.
2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum.
Sources: Expert list

Created: 27 Jul 2020, 12:04 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550

Publications

• 30779713
• 32028018

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