Related Experiment Video
Updated: Feb 18, 2026
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9
Hirohito Shima1, Katrin Koehler2, Yumiko Nomura3
1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
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.
Insights
Myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome is linked to SAMD9 mutations. Somatic reversion mutations in hematopoietic cells may explain the lack of hematological features in some patients.
Area of Science:
- Genetics
- Molecular Biology
- Human Disease
Background:
- Myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome is a rare congenital disorder.
- It is caused by heterozygous mutations in the SAMD9 gene.
- The full spectrum of MIRAGE syndrome phenotypes is not yet fully understood.
Observation:
- Two unrelated patients presented with MIRAGE syndrome-compatible symptoms, but lacked typical hematological features.
- Next-generation sequencing and Sanger sequencing identified two novel de novo SAMD9 mutations (p.[Gln695*; Ala722Glu] and p.[Gln39*; Asp769Gly]) on the same allele in the patients.
- Patient 1's nonsense mutation was somatically acquired, and Patient 2 exhibited skewed X chromosome inactivation, suggesting monoclonality in hematopoietic cells.
Findings:
- In vitro experiments confirmed that the identified SAMD9 missense mutations possess growth-restricting properties, consistent with MIRAGE syndrome.
- The absence of hematological manifestations in these patients is hypothesized to be due to somatic reversion mutations.
- These second-site reversion mutations in the hematopoietic system may counteract the growth repression caused by germline SAMD9 mutations.
Implications:
- This study expands the understanding of the phenotypic variability in MIRAGE syndrome.
- It highlights the potential role of somatic mosaicism and reversion mutations in modulating disease presentation.
- Further research into SAMD9 mutations and their impact on hematopoiesis is warranted.
Related Concept Videos
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:36Mismatch Repair
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:21Cancers Originate from Somatic Mutations in a Single Cell
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...