title: Whole-exome sequence analysis of ataxia telangiectasia-like phenotype.
abstract: A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype.
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Hasegawa
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: m.takagi.ped@tmd.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C526581:CD40LIg fusion protein; D020662:Guanine Nucleotide Exchange Factors; D011993:Recombinant Fusion Proteins; C418483:SIL1 protein, human
keywords: CD40 ligand; DNA damage; Immunodeficiency; Neurodegeneration; SIL1; Whole-exome sequencing