PF213 THE GENETIC LANDSCAPE OF FAMILIAL MDS/AML; RECURRING MUTATIONS IN THE RNA HELICASE DHX34 LEADING TO DEFECTS IN NONSENSE‐MEDIATED RNA DECAY

• Published in: HemaSphere 2019-06, Vol.3 (S1), p.58-n/a
• Main Authors: Rio‐Machin, A., Vulliamy, T., Hug, N., Caceres, J.F., Fitzgibbon, J., Dokal, I.
• Format: Article
• Language: English
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000559068.15425.c6

Background: The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve both the recognition and the management of this group of at risk individuals. Inherited forms account for 3 families, or loci overlapping with other series of potential familial MDS/AML or IBMF syndromes. Germline variants in 22 of the selected 60 genes (37%) have been implicated across a broad range of inherited disorders including T cell‐negative, B cell‐negative, natural killer cell‐negative severe combined immunodeficiency (ADA, p.Gln3∗ and p.Glu88Argfs∗34), Platelet‐type bleeding disorder‐11 (GP6, p.Arg159∗ and p.Met430Lys) and Congenital Dyserythropoietic Anemia Type II (SEC23B, p.Pro542Leu and p.Glu361Asp). Among the non‐syndromic genes, we noted 4 families with variants in TET2, an epigenetic regulator and additional families harboured variants in DHX34, an RNA helicase that has been shown to function in the Nonsense‐mediated RNA decay (NMD) pathway and to co‐purify with the spliceosome, suggesting its potential involvement in pre‐mRNA splicing. All 4 DHX34 variants (p.Tyr515Cys, p.Arg897Cys, p.Asp638Asn and p.Glu444Asp), compromised NMD activity, as shown by their inability to promote phosphorylation of UPF1, which is essential for NMD ac