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Case Reports
. 2018 Feb;55(2):81-85.
doi: 10.1136/jmedgenet-2017-105020. Epub 2017 Nov 24.

Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations

Hirohito Shima  1 , Katrin Koehler  2 , Yumiko Nomura  3 , Kazuhiko Sugimoto  3 , Akira Satoh  3 , Tsutomu Ogata  4 , Maki Fukami  4 , Ramona Jühlen  2 , Markus Schuelke  5 , Klaus Mohnike  6 , Angela Huebner  2 , Satoshi Narumi  1
Affiliations
Case Reports

Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations

Hirohito Shima et al. J Med Genet. 2018 Feb.

Abstract

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.

Keywords: adrenal disorders; genetics; haematology (incl Blood Transfusion); mirage syndrome; reversion mutation.

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Conflict of interest statement

Competing interests: None declared.

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