title: Gain-of-functionSAMD9Lmutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.
abstract: Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations inSAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for eitherSAMD9Lmutation, 3 developed MDS upon loss of the mutatedSAMD9Lallele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional incisSAMD9Ltruncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, intransgerm lineSAMD9Lmissense loss-of-function variant, potentially counteracting theSAMD9Lmutation. Our results demonstrate that gain-of-function mutations in the tumor suppressorSAMD9Lcause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Division of Pediatrics, and.|Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.|Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden.
authors.forename: Josef
authors.initials: J
authors.lastname: Davidsson
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Voss
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rahikkala
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Holmes
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SCC
authors.lastname: Chiang
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Jonna
authors.initials: J
authors.lastname: Komulainen-Ebrahim
authors.affiliation: Department of Neurology, Lund University, Lund, Sweden.
authors.forename: Sorina
authors.initials: S
authors.lastname: Gorcenco
authors.affiliation: Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rundberg Nilsson
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.affiliation: Department of Clinical Chemistry, Oulu University Hospital, Oulu, Finland.
authors.forename: Hannaleena
authors.initials: H
authors.lastname: Kokkonen
authors.affiliation: Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Bryder
authors.affiliation: Department of Clinical Genetics, Lund University, Lund, Sweden.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Möttönen
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Niinimäki
authors.affiliation: Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.|Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden.
authors.forename: Cornelis Jan
authors.initials: CJ
authors.lastname: Pronk
authors.affiliation: Department of Neurology, Lund University, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Puschmann
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Moilanen
authors.affiliation: Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Tedgård
authors.affiliation: Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.|Department of Hematology, Linköping University Hospital, Linköping, Sweden; and.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.affiliation: Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D002897:Chromosomes, Human, Pair 7 / Q000737:chemistry; D060825:Cognitive Dysfunction / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006410:Hematopoiesis / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D007370:Interferon Type I / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010198:Pancytopenia / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; C000621867:SAMD9L protein, human; D025521:Tumor Suppressor Proteins