SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

Abstract

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]

“…As to the diagnosis of primary AI, most points have been shown to be very similar to those in our guideline. As a new form of congenital adrenal hypoplasia, MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) syndrome harboring mutation in SAMD9 has been proposed most recently [98].…”

Myeloid neoplasms with germline DDX41 mutation

“…Familial clustering of myeloid malignancies with autosomal dominant (AD) inheritance has been recognized phenotypically for over 100 years (reviewed in [4]), with the first molecular basis discovered through the identification of germline RUNX1 mutations associated with familial platelet disorder with predisposition to myeloid malignancy in 1999 (FPD-MM, OMIM #601399) [5]. Since that time, and recently accelerated by the advent of next-generation sequencing, a growing number of genes have been associated with AD germline predisposition to myeloid malignancies, including mutations in GATA2 [6] as described by us and others [7], as well as ANKRD26 [8], ETV6 [9], CEBPA [10], RBBP6 [11], TERT, TERC [12], DDX41 [13] and most recently mutations in SAMD9 [14] and SAMD9L [15,16]. This growing recognition and molecular identification of the germline predisposition to a subset of myeloid malignancies has been formalized in the most recent revision to the World Health Organisation guidelines [1].…”

Myeloid Neoplasms with Germline Predisposition

“…Schwartz et al [42] identified these mutations in 17% of pediatric MDS patients. Germline variants in SAMD9 and SAMD9L have been associated with multisystem disorders with a range of systemic abnormalities, including cytopenia, infection, intrauterine restriction of growth, adrenal hypoplasia, abnormal genital phenotypes, progressive cerebellar dysfunction, and enteropathy [43][44][45][46]. To date, there are no reports of expected BM morphology in mutation carriers.…”