title: SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements.
abstract: Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daniela Tiaki
authors.initials: DT
authors.lastname: Uehara
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Nishihara, Japan.
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Chinen
authors.affiliation: Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.affiliation: Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosho
authors.affiliation: Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsubuchi
authors.affiliation: Department of Genetic Counseling, Faculty of Core Research, Ochanomizu University, Tokyo, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Numabe
authors.affiliation: Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Shinji
authors.identifier: http://orcid.org/0000-0001-6911-3351
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Education Center, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Makita
authors.affiliation: Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C470384:PPFIA2 protein, human