title: An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities.
abstract: The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (>3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Nottingham Clinical Genetics Service, Nottingham City Hospital, Nottingham, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilsdon
authors.affiliation: West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, UK.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: 1] Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes 7, Nantes, France [2] INSERM, UMR915, L'institut du Thorax, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Erlandsson
authors.affiliation: Nottingham Clinical Genetics Service, Nottingham City Hospital, Nottingham, UK.
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sangu
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimojima
authors.affiliation: 1] Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes 7, Nantes, France [2] INSERM, UMR915, L'institut du Thorax, Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Samuelsson
authors.affiliation: 1] Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden [2] Department of Medical and Clinical Genetics, Sahlgrenska Academy, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden [3] Department of Clinical Genetics, University Hospital Linköping, Linköping, Sweden.
authors.forename: Margarita
authors.initials: M
authors.lastname: Stefanova
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001526:Behavioral Symptoms / Q000150:complications / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D009123:Muscle Hypotonia / Q000150:complications / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics; D010641:Phenotype; D017384:Sequence Deletion; D012729:Sex Chromosome Aberrations; D049951:X Chromosome Inactivation
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human