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.
- adrenal disorders
- haematology (incl Blood Transfusion)
- mirage syndrome
- reversion mutation
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HS and KK contributed equally.
Contributors YN, KS, AS and KM clinically characterised the patients. TO, MF and KK collected genetic samples. HS, KK, RJ and MS conducted sequencing experiments. HS conducted expression experiments. KK and SN created the design of the study. HS and SN wrote the manuscript with critical inputs from KK, AH and MS. All authors read and approved the final manuscript.
Funding This work was partly supported by a DFG grant HU 895/5-2 (Clinical Research Unit 252), a DFG grant KO 3588/2-1, Takeda Science Foundation, Japan Intractable Diseases (Nanbyo) Research Foundation, the Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (3905-A02) and a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development, AMED.
Competing interests None declared.
Patient consent Obtained.
Ethics approval National Center for Child Health and Development, Medical Faculty, Technische Universität Dresden.
Provenance and peer review Not commissioned; externally peer reviewed.
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