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

Hirohito Shima, Katrin Koehler, Yumiko Nomura, Kazuhiko Sugimoto, Akira Satoh, Tsutomu Ogata, Maki Fukami, Ramona Jühlen, Markus Schuelke, Klaus Mohnike, Angela Huebner, Satoshi Narumi

研究成果: Article査読

30 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)81-85
ページ数5
ジャーナルJournal of medical genetics
55
2
DOI
出版ステータスPublished - 2018 2 1
外部発表はい

ASJC Scopus subject areas

  • 遺伝学
  • 遺伝学(臨床)

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