Submission Details

MTAP (MethylThioAdenosine Phosphorylase) was first reported in relation to autosomal dominant diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH [MIM 112250]) in 2012 (Camacho-Vanegas et al., PMID: 22464254). However, prior to this the critical locus was identified through linkage (Martignetti et al 1999) and reports of the condition had been circulating since its early identification (Arnold, 1973). DMS-MFH presents with unique bone dysplasia phenotypes that result in fractures and poor healing, as well as progressive wasting, cataracts and muscular dystrophy. Approximately 35% of affected individuals develop bone sarcoma. The reported variants are synonymous (predicted silent) variants that affect splicing of the MTAP gene and result in numerous isoforms with negative consequences on MTAP functions. Evidence supporting this gene-disease relationship includes case-level, segregation and experimental data. Variants in MTAP have been reported in at least 5 probands in 1 publication (PMID:22464254) summarizing multiple prior publications. MTAP variants display a clear autosomal dominant inheritance pattern. The mechanism for disease is altered function and is still being investigated. 5.5 points (2.5 points case level data and 3 points segregation) were received in the genetic evidence section. Experimental evidence is limited to 2.75 points including expression studies including RNA analysis from patients, in vitro functional assays and has some support from a mouse model (PMIDs:19567676;22464254;11895909). In addition, around 1/3 of osteosarcomas (35%) display loss of MTAP. While heterozygous knockout of MTAP in mice does not cause osteosarcoma, these mice display T-cell lymphoma and the homozygous knockout is embryonic lethal, which indicates the essential nature of the MTAP gene. In summary, there is moderate evidence to support the relationship between MTAP and diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH).