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Reversion SAMD9 Mutations Modifying Phenotypic Expression of MIRAGE Syndrome and Allowing Inheritance in a Usually de
Florence Roucher-Boulez1,2,3,4, Delphine Mallet1,3, Nicolas Chatron2,5,6
1Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
Abstract:
Context: MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high mortality. It is caused by a heterozygous gain of function mutation in the growth repressor gene SAMD9. The increasing number of reported cases displays a spectrum of phenotypes that may be explained by an adaptation mechanism, with appearance of a somatic second hit mutation with revertant effects. Objective: To determine the genetic basis of the MIRAGE syndrome rapidly corrected in a living and healthy 46,XY patient. Subjects and Methods: A 46,XY patient born with growth restriction and disorders of sex development had thrombocytopenia and necrotizing enterocolitis during the neonatal period suggestive of the syndrome. Faced with the rapid improvement of the patient's phenotype, an adaptation mechanism was sought by repeating genetic analysis at different ages; her parents also underwent genetic analysis. Results: The previously described p.(Thr778Ile) mutation was identified and surprisingly transmitted by the asymptomatic mother in this usually de novo syndrome. To explain the rapid improvement of the patient's phenotype and absence of symptoms in the mother, an adaptation mechanism was sought. For the mother, a non-sense mutation was found (p.(Arg221*)) in cis, and most likely appeared in utero. It was not transmitted to her child. The child harbored a different non-sense mutation (p.(Arg285*)) that most likely appeared near day 20. Conclusions: We show that pathogenic variants can be inherited from a healthy parent as the adaptation mechanism may arise early in life and mask symptoms. Presence of revertant mosaicism mutations could explain "incomplete penetrance" in other disease. For a better management and outcomes in patients, appearance of this natural gene therapy should be sought by repeating genetic analysis.
Insights
MIRAGE syndrome, caused by SAMD9 mutations, can be inherited from asymptomatic parents. Revertant mosaicism mutations may explain symptom masking and rapid recovery in affected children.
Area of Science:
- Genetics
- Molecular Biology
- Pediatrics
Background:
- MIRAGE syndrome is a severe, often fatal, multisystem disorder caused by gain-of-function mutations in the SAMD9 gene.
- Phenotypic variability and spontaneous recovery suggest an adaptation mechanism involving secondary genetic events.
Observation:
- A 46,XY patient with severe neonatal symptoms suggestive of MIRAGE syndrome showed rapid, spontaneous improvement.
- Genetic analysis revealed the patient inherited a SAMD9 mutation from her asymptomatic mother, who carried a different, likely in utero, second hit mutation (p.(Arg221*)).
- The patient also developed a distinct second hit mutation (p.(Arg285*)) around day 20, suggesting an early adaptive response.
Findings:
- Pathogenic SAMD9 variants can be inherited from phenotypically normal parents.
- Somatic second hit mutations, acting as a natural gene therapy, can arise early in life, leading to symptom amelioration and potentially explaining incomplete penetrance.
- The study identified specific nonsense mutations (p.(Arg221*) in the mother and p.(Arg285*) in the child) contributing to the adaptive mechanism.
Implications:
- Understanding revertant mosaicism is crucial for diagnosing and managing MIRAGE syndrome.
- Repeating genetic analyses may reveal adaptive mutations, improving patient prognosis and outcomes.
- This mechanism of natural gene therapy could offer insights into managing other genetic disorders with incomplete penetrance.
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