Skeletal dysplasiaGene: PFN1
Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition. Wait for confirmation of this gene's involvement in Paget disease of bone in probands with different variants or that are confirmed as unrelated to the cases already described.
Created: 21 Jan 2021, 2:43 p.m. | Last Modified: 21 Jan 2021, 2:45 p.m.
Panel Version: 2.73
Associated with Amyotrophic lateral sclerosis 18 in OMIM, a neurological condition.
3 cases but all with the same variant, and all from Italy and some functional data:
PMID: 32392277 Merlotti et al 2020 - report a large, 3 generation Italian family with 8 members with Paget disease of bone (PDB). Using WES a variant in PFN1 ( cDNA.938_941delTGAC, p.D107Rfs*3) resulting in a truncated protein was detected which segregated with all affected members of the family, and in addition in 1 young apparently unaffected sibling. This family comes from the same region of Italy as the one reported by Scotto di Carlo. Through sequencing of PFN1 in unrelated individuals found through the Italian PDB Registry, an additional patient with the same p.D107Rfs*3 variant was found. An increase in osteoclast size and number of nuclei were observed upon PFN1 silencing in mouse, and osteoclasts from the PFN1 silenced mice showed an increase in resorptive activity when cultured on bone slices.
PMID: 31991009 Scotto di Carlo et al 2020 - report a 4‐generation family in which 11 individuals had been diagnosed with PDB, with 3 PDB subjects who developed osteosarcoma at pagetic bones. Using WES a c.318_321delTGAC heterozygous mutation (p.Asp107Argfs*2) in the PFN1 gene in was identified. Additionally analysis of copy number assays found that one copy of PFN1 (heterozygous) was lost in 4 of 218 pagetic individuals who were part of the Italian PDB biobank. Functional studies showed that PFN1 loss affects osteoclast differentiation and resorption
Created: 21 Jan 2021, 2:39 p.m. | Last Modified: 21 Jan 2021, 2:39 p.m.
Panel Version: 2.71
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
bone Paget disease MONDO:0005382
A new phenotype association for this gene has been reported: Paget’s disease of bone (PDB).
Haploinsuffciency has been linked to PDB in 2 families with the same truncating frameshift variant (unsure if the families are related, both families are from the same region in Italy). Functional studies of this truncating variant showed abnormal protein aggregates (PMID: 32392277, 31991009). An osteoclast-specific conditional null mouse model confirmed the skeletal phenotype (PMID: 31346562). Missense variants in this gene have been previously associated with ALS (PMID: 22801503). Due to these different phenotype associations, it has been suggested that this gene can cause multisystem proteinopathy (PMID: 32589291).
Created: 5 Oct 2020, 9:20 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paget’s disease of bone
Phenotypes for gene: PFN1 were changed from Paget’s disease of bone to Paget’s disease of bone; bone Paget disease MONDO:0005382
Gene: pfn1 has been classified as Amber List (Moderate Evidence).
gene: PFN1 was added gene: PFN1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PFN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PFN1 were set to 32392277; 31991009; 31346562; 32589291; 22801503 Phenotypes for gene: PFN1 were set to Paget’s disease of bone Review for gene: PFN1 was set to AMBER