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Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing.
Gene. 2014 Aug 10; 546(2):425-9.GENE

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.

CASE PRESENTATION

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.

CONCLUSION

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+Show Affiliations

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.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.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.Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea. Electronic address: jongyeon.shin@gmail.com.Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address: neuroandy@korea.com.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.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.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.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.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.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24914498

Citation

Lim, Byung Chan, et al. "Hoyeraal-Hreidarsson Syndrome With a DKC1 Mutation Identified By Whole-exome Sequencing." Gene, vol. 546, no. 2, 2014, pp. 425-9.
Lim BC, Yoo SK, Lee S, et al. Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. Gene. 2014;546(2):425-9.
Lim, B. C., Yoo, S. K., Lee, S., Shin, J. Y., Hwang, H., Chae, J. H., Hwang, Y. S., Seo, J. S., Kim, J. I., & Kim, K. J. (2014). Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. Gene, 546(2), 425-9. https://doi.org/10.1016/j.gene.2014.06.011
Lim BC, et al. Hoyeraal-Hreidarsson Syndrome With a DKC1 Mutation Identified By Whole-exome Sequencing. Gene. 2014 Aug 10;546(2):425-9. PubMed PMID: 24914498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. AU - Lim,Byung Chan, AU - Yoo,Seong-Keun, AU - Lee,Seungbok, AU - Shin,Jong-Yeon, AU - Hwang,Hee, AU - Chae,Jong Hee, AU - Hwang,Yong Seung, AU - Seo,Jeong-Sun, AU - Kim,Jong-Il, AU - Kim,Ki Joong, Y1 - 2014/06/07/ PY - 2014/02/13/received PY - 2014/05/23/revised PY - 2014/06/06/accepted PY - 2014/6/11/entrez PY - 2014/6/11/pubmed PY - 2014/9/5/medline KW - DKC1 KW - Dyskeratosis congenita KW - Hoyeraal–Hreidarsson syndrome KW - Telomere dysfunction KW - Whole-exome sequencing SP - 425 EP - 9 JF - Gene JO - Gene VL - 546 IS - 2 N2 - 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. CASE PRESENTATION: 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. CONCLUSION: 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. SN - 1879-0038 UR - https://wwww.unboundmedicine.com/medline/citation/24914498/Hoyeraal_Hreidarsson_syndrome_with_a_DKC1_mutation_identified_by_whole_exome_sequencing_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(14)00675-1 DB - PRIME DP - Unbound Medicine ER -