TY - JOUR T1 - Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2017-105020 SP - jmedgenet-2017-105020 AU - Hirohito Shima AU - Katrin Koehler AU - Yumiko Nomura AU - Kazuhiko Sugimoto AU - Akira Satoh AU - Tsutomu Ogata AU - Maki Fukami AU - Ramona Jühlen AU - Markus Schuelke AU - Klaus Mohnike AU - Angela Huebner AU - Satoshi Narumi Y1 - 2017/11/24 UR - http://jmg.bmj.com/content/early/2017/11/24/jmedgenet-2017-105020.abstract N2 - Background Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated.Methods and results We describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations.Conclusions Acquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations. ER -