title: Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.
abstract: The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1,USP34,BCL11A, andREL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients' lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion ofXPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients' LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients' LCLs. Knockdown ofxpo1a,rel,bcl11aa, andbcl11abresulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicatesXPO1,REL, andBCL11Aas candidate genes for 2p15p16.1 microdeletion syndrome.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Hani
authors.initials: H
authors.lastname: Bagheri
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Chansonette
authors.initials: C
authors.lastname: Badduke
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Colnaghi
authors.affiliation: Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Iga
authors.initials: I
authors.lastname: Abramowicz
authors.affiliation: Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.affiliation: University of Texas at Dallas, Dallas, Texas, USA.
authors.forename: Jiadi
authors.initials: J
authors.lastname: Wen
authors.affiliation: St. Luke's Children's Hospital, Boise, Idaho, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wildin
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada.
authors.forename: Malgorzata Jm
authors.initials: MJ
authors.lastname: Nowaczyk
authors.affiliation: St. Luke's Mountain States Tumor Institute, Boise, Idaho, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Eichmeyer
authors.affiliation: Department of Medical Genetics, UBC, Vancouver, British Columbia, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Medical Genetics, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Sally
authors.initials: S
authors.lastname: Martell
authors.affiliation: Department of Ophthalmology, UBC, Vancouver, British Columbia, Canada.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Medical Genetics, UBC, Vancouver, British Columbia, Canada.
authors.forename: Suzanne Me
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.affiliation: Department of Ophthalmology, UBC, Vancouver, British Columbia, Canada.
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Gregory-Evans
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Evica
authors.initials: E
authors.lastname: Rajcan-Separovic
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D028884:Karyopherins / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012097:Repressor Proteins; D015027:Zebrafish; D000097606:Exportin 1 Protein
chemical_list: D002352:Carrier Proteins; D028884:Karyopherins; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000097606:Exportin 1 Protein; C486563:BCL11A protein, human