Skeletal dysplasia

Gene: ZNF687

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

Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review.

Created: 10 Nov 2021, 10:49 a.m. | Last Modified: 10 Nov 2021, 10:49 a.m.

Panel Version: 2.152

Associated with Paget disease of bone 6 #616833 (AD) in OMIM. Paget's disease of bone (PDB) is a bone disorder characterized by focal areas of increased bone resorption coupled with a disorganized increase in bone formation (from PMID: 29493781). In some cases PDB is also associated with giant cell tumor (GCT).

Founder variant c.2810C>G (p.Pro937Arg) associated with PDB/GCT in many families from Southern Italy, but also in one family with a different haplotype. 3 other different variants have also been identified in this gene in 2 sporadic and 1 familial case of PDB.

PMID: 29493781 - Divisato et al 2018 - report 10 out of 30 of patients with PDB recruited from Avellino, Southern Italy with ZNF687 variants. In all familial cases (8 patients) the p.Pro937Arg variant was found. 2 novel mutations c.1994C>T, p.Pro665Leu and c.2350C>G, p.Gln784Glu were also found in two sporadic cases with a milder phenotype and later onset (55 years and 63 years, respectively). The patients with the p.Pro937Arg variant had the same allelic composition while those with the other two variants had a different haplotype.

PMID: 26849110 - Divisato et al 2016 - using WES they identified a heterozygous c.2810C>G (p.Pro937Arg) missense variant that segregated with the clinical phenotype in a family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites. No variants were found in other PDB-related/PDB similar syndrome genes (SQSTM1, TNFRSF11A, TNFRSF11B, VCP). The c.2810C>G variant was then found in 7 additional unrelated individuals with PDB complicated with GCT, 4 from the same area of Southern Italy as family 1, and 3 were North-American individuals of European descent. All but 1 were found to have identical variants in surrounding genes (i.e. same haplotype) but the occurrence of the c.2810C>G mutation on a different haplotype in one individual provides the genetic evidence that this mutation is likely causative. In addition, another variant in ZNF687 (c.725G>T (p.Ser242Ile)) was found in 4 affected individuals in another family, but not in 3 unaffected family members.

Also mentioned by reviewer - PMID: 28968976 - Divisato et al 2017 - identify H3F3A mutations in a giant cell tumor (GCT) cohort but no mutations in the ZNF687 gene were found in these patients.

Created: 10 Nov 2021, 10:48 a.m. | Last Modified: 10 Nov 2021, 10:48 a.m.

Panel Version: 2.151

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

Phenotypes
Paget disease of bone 6, OMIM:616833

Publications

• 29493781
• 26849110

Green List (high evidence)

Missense mutation c.2810C>G (p.Pro937Arg) alters the nuclear-ctyoplasmic balance of ZNF687 by generating a stronger nuclear localisation signal thereby acting as a gain-of-function mutation.
Sources: Other, Research

Created: 26 Oct 2021, 1:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Paget Disease of Bone with associated Giant Cell Tumour.

Publications

• PMID: 29493781, PMID: 28968976, PMID: 26849110

Mode of pathogenicity
Other