title: Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing.
abstract: BACKGROUND
  Hoyeraal-Hreidarsson syndrome is a severe multisystem disorder that is characterized by bone-marrow failure, intrauterine growth retardation, microcephaly, immunodeficiency, and cerebellar atrophy. This rare disease shares clinical features with dyskeratosis congenita and, together, they are recognized as a group of disorders caused by telomere dysfunction. As the genetic background of dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome has expanded rapidly, multiple causative genes and inheritance patterns pose a great challenge to their genetic diagnosis.
  
  
  METHODS
  A 3-month-old boy was referred for head titubation and tremulous movements of the trunk. Multiple petechiae also developed on his face and trunk at the age of 5 months. Extensive evaluation, including brain magnetic resonance imaging, hematologic tests, and bone-marrow evaluation, revealed cerebellar atrophy and aplastic anemia. His elder brother exhibited a similar clinical presentation and died from sepsis after hematopoietic stem cell transplantation. Although skin pigmentation or nail dystrophy was not evident, Hoyeraal-Hreidarsson syndrome was suggested as a differential diagnosis. Instead of the conventional gene-specific approach with Sanger sequencing, we used whole-exome sequencing for the genetic diagnosis of this patient with possible Hoyeraal-Hreidarsson syndrome and successfully identified a missense mutation (c.146C>T, p.Thr49Me) in DKC1.
  
  
  CONCLUSIONS
  This case suggests that whole-exome sequencing is particularly useful for the genetic diagnosis of extremely rare diseases with genetic heterogeneity, although there are many limitations, including cost and uneven or suboptimal coverage, to the application of this method as a routine genetic diagnosis.
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: prabbit7@snu.ac.kr.
authors.forename: Byung Chan
authors.initials: BC
authors.lastname: Lim
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea. Electronic address: ysk819@hanmail.net.
authors.forename: Seong-Keun
authors.initials: SK
authors.lastname: Yoo
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea. Electronic address: for3guy@naver.com.
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea. Electronic address: jongyeon.shin@gmail.com.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: neuroandy@korea.com.
authors.forename: Hee
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: chaeped1@snu.ac.kr.
authors.forename: Jong Hee
authors.initials: JH
authors.lastname: Chae
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: childnr@snu.ac.kr.
authors.forename: Yong Seung
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea; Macrogen Inc., Seoul, Republic of Korea; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea. Electronic address: jeongsun@snu.ac.kr.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: jongil@snu.ac.kr.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: pednr@plaza.snu.ac.kr.
authors.forename: Ki Joong
authors.initials: KJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins
keywords: DKC1; Dyskeratosis congenita; Hoyeraal–Hreidarsson syndrome; Telomere dysfunction; Whole-exome sequencing