title: CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids.
abstract: Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 3 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA feichler@partners.org.
authors.forename: Florian S
authors.initials: FS
authors.lastname: Eichler
authors.affiliation: 4 BGI-Shenzhen, Shenzen 518083, China 5 Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Li
authors.affiliation: 6 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 7 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 8 Department of Paediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.affiliation: 9 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Caruso
authors.affiliation: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bjonnes
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 3 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Pan
authors.affiliation: 11 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Booker
authors.affiliation: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 12 Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Lane
authors.affiliation: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Tare
authors.affiliation: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
authors.forename: Irma
authors.initials: I
authors.lastname: Vlasac
authors.affiliation: 6 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 7 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 8 Department of Paediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA 13 Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: 4 BGI-Shenzhen, Shenzen 518083, China 5 Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 6 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 7 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 8 Department of Paediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA 12 Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D046528:Chimerism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: dementia; leukodystrophy; neurodegeneration; neuroinflammation; whole exome sequencing