title: Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.
abstract: It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
authors.forename: Federica
authors.initials: F
authors.lastname: Buonocore
authors.forename: Peter
authors.initials: P
authors.lastname: Kühnen
authors.forename: Jenifer P
authors.initials: JP
authors.lastname: Suntharalingham
authors.forename: Ignacio
authors.initials: I
authors.lastname: Del Valle
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
authors.forename: Harald
authors.initials: H
authors.lastname: Stachelscheid
authors.forename: Noushafarin
authors.initials: N
authors.lastname: Khajavi
authors.forename: Mohammed
authors.initials: M
authors.lastname: Didi
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.forename: Oliver
authors.initials: O
authors.lastname: Blankenstein
authors.forename: Annie M
authors.initials: AM
authors.lastname: Procter
authors.forename: Paul
authors.initials: P
authors.lastname: Dimitri
authors.forename: Jerry K H
authors.initials: JKH
authors.lastname: Wales
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghirri
authors.forename: Dieter
authors.initials: D
authors.lastname: Knöbl
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: George K
authors.initials: GK
authors.lastname: Kokai
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.forename: Deborah
authors.initials: D
authors.lastname: Morrogh
authors.forename: Dale A
authors.initials: DA
authors.lastname: Moulding
authors.forename: Shane A
authors.initials: SA
authors.lastname: McKee
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
mesh_terms: D000309:Adrenal Insufficiency / Q000151:congenital* / Q000235:genetics / Q000401:mortality; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D015331:Cohort Studies; D016368:Frameshift Mutation / Q000235:genetics; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D011506:Proteins / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human