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Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes
Jasmine C. Wong, … , Kevin Shannon, Jeffery M. Klco
Jasmine C. Wong, … , Kevin Shannon, Jeffery M. Klco
Published July 25, 2018
Citation Information: JCI Insight. 2018;3(14):e121086. https://doi.org/10.1172/jci.insight.121086.
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Research Article Hematology

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

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Abstract

Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families.

Authors

Jasmine C. Wong, Victoria Bryant, Tamara Lamprecht, Jing Ma, Michael Walsh, Jason Schwartz, Maria del pilar Alzamora, Charles G. Mullighan, Mignon L. Loh, Raul Ribeiro, James R. Downing, William L. Carroll, Jeffrey Davis, Stuart Gold, Paul C. Rogers, Sara Israels, Rochelle Yanofsky, Kevin Shannon, Jeffery M. Klco

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Figure 1

SAMD9 and SAMD9L variants identified in 5 MLSM7 families.

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SAMD9 and SAMD9L variants identified in 5 MLSM7 families.
Schematic dia...
Schematic diagram of the locations of germline mutations and potential revertants with respect to the predicted domains of SAMD9 (NM_017654) and SAMD9L (NM_152703) proteins based on Mekhedov et al. (12). Germline mutations (top) and potential revertants (bottom) are shown. Mutations and revertants are color coded for each family (1: green, 2: orange, 3: purple, 4: blue, 5: red). SAM, sterile α motif domain; AlbA, acetylation lowers binding affinity; DNA-binding domain; PPR, pentatricopeptide repeat; SIR2, silent mating–type information regulation 2; P-loop NTPase, P-loop–containing nucleoside triphosphate hydrolase; TPR, tetratricopeptide repeat–containing domain; OB, oligonucleotide/oligosaccharide–binding fold domain. Figure not drawn to scale.

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ISSN 2379-3708

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