Skeletal dysplasiaGene: ZNF687
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
Paget disease of bone 6, OMIM:616833
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
Paget Disease of Bone with associated Giant Cell Tumour.
Mode of pathogenicity
Tag Q4_21_NHS_review tag was added to gene: ZNF687.
Phenotypes for gene: ZNF687 were changed from Paget Disease of Bone with associated Giant Cell Tumour. to Paget disease of bone 6, OMIM:616833
Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110
Gene: znf687 has been classified as Amber List (Moderate Evidence).
Tag Q4_21_rating tag was added to gene: ZNF687.
gene: ZNF687 was added gene: ZNF687 was added to Skeletal dysplasia. Sources: Other,Research Mode of inheritance for gene: ZNF687 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110 Phenotypes for gene: ZNF687 were set to Paget Disease of Bone with associated Giant Cell Tumour. Penetrance for gene: ZNF687 were set to unknown Mode of pathogenicity for gene: ZNF687 was set to Other Review for gene: ZNF687 was set to GREEN