SAMD9 – MIRAGE syndrome

MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) is a rare multisystem disorder caused by heterozygous gain-of-function variants in the SAMD9 gene. Initial discovery in 2017 demonstrated de novo SAMD9 mutations in eight unrelated children with intrauterine growth restriction, adrenal and gonadal hypoplasia, bone marrow failure, and high mortality, establishing SAMD9 as the causal gene (PMID:28346228). Subsequent case reports and series have confirmed SAMD9 pathogenicity across diverse populations, solidifying the genetic etiology of MIRAGE syndrome.

Genetic evidence comprises over 30 unrelated probands with de novo SAMD9 gain-of-function variants identified by targeted exome or whole genome sequencing (PMID:29506479, PMID:28346228). The spectrum includes recurrent missense changes (e.g., c.2944C>T (p.Arg982Cys)), splice and frameshift mutations, with occasional familial transmission modified by cis revertant mosaicism (PMID:31572304). Variants predominantly arise de novo, consistent with an autosomal dominant inheritance mode and strong genotype–phenotype correlation.

Segregation studies are limited by de novo occurrence, but one reported transmission involved a healthy mosaic mother and affected child, illustrating somatic rescue mechanisms. Somatic second-hit mutations (nonsense or frameshift) or monosomy 7/7q- in bone marrow cells rescue the proliferative block, prolong survival, and highlight tissue-specific adaptation (PMID:28346228). No stable multigenerational segregation has been observed beyond mosaic parental cases.

Functional assays demonstrate that SAMD9 gain-of-function variants enhance the protein’s growth-repressor activity, leading to endosomal trafficking defects and global translational inhibition in patient-derived cells and engineered iPSC models (PMID:35046037, PMID:39276527). In vitro expression of mutant SAMD9 reduces cellular proliferation, increases apoptosis, and disrupts endosome–lysosome fusion concordant with clinical manifestations of tissue hypoplasia and immunodeficiency.

Clinically, patients present with variable myelodysplasia, adrenal insufficiency, enteropathy (intractable diarrhea), genital anomalies, growth delay, and recurrent infections. Adrenal crisis in the neonatal period is life-threatening but amenable to early hormone replacement. Enteropathy responds variably to dietary and enzyme supplementation, while hematologic complications may require hematopoietic stem cell transplantation, albeit with mixed outcomes (PMID:31620126).

Integration of genetic and experimental data yields a definitive gene–disease association for SAMD9 and MIRAGE syndrome. Diagnostic genetic testing for SAMD9 variants in infants with adrenal hypoplasia and extra-adrenal features is recommended. Key take-home: early molecular diagnosis enables lifesaving hormone therapy and tailored monitoring of hematologic and gastrointestinal complications.

References

• The Journal of clinical investigation • 2017 • Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. PMID:28346228
• BMC medical genetics • 2018 • A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing. PMID:29506479
• Trends in molecular medicine • 2019 • MIRAGE Syndrome: Phenotypic Rescue by Somatic Mutation and Selection. PMID:31624021
• Frontiers in immunology • 2019 • Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement. PMID:31620126
• Human genome variation • 2020 • MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene. PMID:32194975
• Proceedings of the National Academy of Sciences of the United States of America • 2022 • Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L. PMID:35046037

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