Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome
by Sarah R. Poll, Renan Martin, Elizabeth Wohler, Elizabeth S. Partan, Elizabeth Walek, Shaima Salman, Daniel Groepper, Lisa Kratz, Mirlene Cernach, Reynaldo Jesus-Garcia, Chad Haldeman-Englert, Yoon Jae Choi, Carol D. Morris, Bernard Cohen, Julie Hoover-Fong, David Valle, Gregg L. Semenza, Nara L. M. Sobreira Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants inIDH1 andIDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants inHIF1A, 6 had rare germline missense variants inVHL, and 3 hadIDH1 variants including 2 with mosaicIDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found tha...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Sarah R. Poll Source Type: research
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