Reversion SAMD9 Mutations Modifying Phenotypic Expression of MIRAGE Syndrome and Allowing Inheritance in a Usually de novo Disorder

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.

Keywords: MIRAGE syndrome; SAMD9; disorders of sex development; fetal growth retardation; reversion mutations; revertant mutations; small for gestational age.

Figure 1

Patient's growth chart compared to the French reference Boy's growth chart.

Figure 2

Pedigree and partial chromatograms showing the SAMD9 mutations over time. The segregation of the gain of function (p.Thr778Ile) and the appearance of the reversion mutation (p.Arg221^*, p.Arg285^*) is shown over time. Above the time frame (corresponding to the age of the patient when DNA was sampled), next to the pedigree are shown a scheme of the haplotype in different cells: in blue is the wild type haplotype, in yellow the haplotype with a gain of function mutation and in green the haplotype with a gain of function disrupted by a loss of function mutation in cis. In the pedigree the symbol dashed indicates absence or correction of the symptoms found in MIRAGE syndrome. Under the time frame, partial Sanger chromatograms show presence or absence of the mutations at 5 days and 14 years of age for the proband. The reference sequence is highlighted in blue. At the 5 days old of the proband, the revertant mutation p.Arg221^* was found in cis in the mother but not transmitted to her children, confirming the adaptation mechanism in the mother occurred somatically and did not concern all tissues, at least the gonads. The correction of the symptoms around day 20 for the proband suggests the adaptive mechanism by appearance of the p.Arg285^* mutation was enough at this age, but it was only confirmed on a sample at 14 years old. WT, wild-type; gof, gain of function mutation; lof, loss of function mutation.