title: Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease.
abstract: Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG-modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole-Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chromosome 12q23 that encompasses part of CHST11 (encoding chondroitin-4-sulfotransferase 1) and an embedded microRNA (MIR3922). The deletion was homozygous in the proband but not in each of three unaffected siblings. Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events. Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development. Our findings also potentially reveal an unexpected role for CHST11 and/or MIR3922 as tumor suppressors whose disruption may contribute to malignant lymphoproliferative disease.
authors.affiliation: Dana Farber Cancer Institute, Brigham and Women's Hospital Boston, Massachusetts.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Chopra
authors.affiliation: Broad Institute, Brigham and Women's Hospital Cambridge, Massachusetts.
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: Department of Medical Genetics, Yeditepe University School of Medicine Istanbul, Turkey ; Genetic Training Program, Harvard Medical School Boston, Massachusetts ; Partners Healthcare Center for Personalized Medicine Cambridge, Massachusetts.
authors.forename: Hatice
authors.initials: H
authors.lastname: Duzkale
authors.affiliation: Partners Healthcare Center for Personalized Medicine Cambridge, Massachusetts.
authors.forename: Heather
authors.initials: H
authors.lastname: McLaughlin
authors.affiliation: Geisinger Genomic Medicine Center, Geisinger Medical Center Danville, Pennsylvania.
authors.forename: Monica
authors.initials: M
authors.lastname: Giovanni
authors.affiliation: The Jackson Laboratory for Genomic Medicine Farmington, Connecticut.
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cardiovascular Division, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Nathan
authors.initials: N
authors.lastname: Stitziel
authors.affiliation: University of Massachusetts Medical School Worchester, Massachusetts.
authors.forename: Joyce
authors.initials: J
authors.lastname: Fingeroth
authors.affiliation: Beth Israel Deaconess Medical Center Boston, Massachusetts.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Joyce
authors.affiliation: Partners Healthcare Center for Personalized Medicine Cambridge, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lebo
authors.affiliation: Partners Healthcare Center for Personalized Medicine Cambridge, Massachusetts.
authors.forename: Heidi
authors.initials: H
authors.lastname: Rehm
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts.
authors.forename: Dana
authors.initials: D
authors.lastname: Vuzman
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Maas
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.affiliation: Dana Farber Cancer Institute, Brigham and Women's Hospital Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Cassa
keywords: CHST11; MIR3922; inherited lymphoproliferative disorder; malignant lymphoproliferative disorder; skeletal malformation