Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma


IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

Online
ISSN
2191-0251
See all formats and pricing
More options …
Volume 30, Issue 4

Issues

Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

Qingwen Zeng
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Yanjie Fan
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Lili Wang
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Zhuo Huang
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Xuefan Gu
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Yongguo Yu
  • Corresponding author
  • Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R. China
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2017-03-17 | DOI: https://doi.org/10.1515/jpem-2016-0333

Abstract

Background:

Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies.

Case presentation:

Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient’s blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient’s c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up.

Conclusions:

Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

Keywords: atypical; mucopolysaccharidosis IIIB; next-generation sequencing (NGS); whole exome sequencing (WES)

References

  • 1.

    Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF. The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA 1996;93:6101–5.Google Scholar

  • 2.

    Hara A, Kitazawa N, Taketomi T. Abnormalities of glycosphingolipids in mucopolysaccharidosis type III B. J Lipid Res 1984;25:175–84.Google Scholar

  • 3.

    Haust MD, Gordon BA. Ultrastructural and biochemical aspects of the Sanfilippo syndrome – type III genetic mucopolysaccharidosis. Connect Tissue Res 1986;15:57–64.Google Scholar

  • 4.

    Murata R, Nakajima S, Tanaka A, Miyagi N, Matsuoka O, et al. MR imaging of the brain in patients with mucopolysaccharidosis. AJNR Am J Neuroradiol 1989;10:1165–70.Google Scholar

  • 5.

    Valstar MJ, Ruijter GJ, van Diggelen OP, Poorthuis BJ, Wijburg FA. Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31:240–52.Google Scholar

  • 6.

    Cooper DN, Chen JM, Ball EV, Howells K, Mort M, et al. Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum Mutat 2010;31:631–55.Google Scholar

  • 7.

    Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010;26:589–95.Google Scholar

  • 8.

    Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, et al. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics 2009;25:2283–5.Google Scholar

  • 9.

    DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011;43:491–8.Google Scholar

  • 10.

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297–303.Google Scholar

  • 11.

    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.Google Scholar

  • 12.

    von Figura K, Lögering M, Kresse H. Serum alpha-N-acetylglucosaminidase: determination, characterization, and corrective activity in Sanifilippo B fibroblasts. Z Klin Chem Klin Biochem 1975;13:285–9.Google Scholar

  • 13.

    Zhao HG, Aronovich EL, Whitley CB. Genotype-phenotype correspondence in Sanfilippo syndrome type B. Am J Hum Genet 1998;62:53–63.Google Scholar

  • 14.

    Valstar MJ, Bruggenwirth HT, Olmer R, Wevers RA, Verheijen FW, et al. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J Inherit Metab Dis 2010;33:759–67.Google Scholar

  • 15.

    Heldermon CD, Ohlemiller KK, Herzog ED, Vogler C, Qin E, et al. Therapeutic efficacy of bone marrow transplant, intracranial AAV-mediated gene therapy, or both in the mouse model of MPS IIIB. Mol Ther 2010;18:873–80.Google Scholar

  • 16.

    Fu H, Samulski RJ, McCown TJ, Picornell YJ, Fletcher D, et al. Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. Mol Ther 2002;5:42–9.Google Scholar

  • 17.

    Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 2012;4:118ra10.Google Scholar

  • 18.

    Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, et al. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med 2012;4:138ra78.Google Scholar

  • 19.

    Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 2012;49:353–61.Google Scholar

About the article

Corresponding author: Yongguo Yu, MD, PhD, Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Room 801 Sci&Edu Bldg, 1665 Kongjiang Rd, Yangpu district, Shanghai, 200092, P.R. China, Phone: +86-21-25076453, Fax: +86-21-25076453


Received: 2016-08-20

Accepted: 2017-01-31

Published Online: 2017-03-17

Published in Print: 2017-04-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This study was supported by the “National Key Technology R&D Program” (2012BAI09B04, to GXF); the Special Basic Work of Science and Technology (2014FY110700 for GXF); the “Innovation Fund for Translational Medicine Plan” from the Shanghai Jiao Tong University School of Medicine (No. 15ZH3003, to YYG); and grant from the National Natural Science Foundation of China (No. 44107690, to ZQW; 81670812, to YYG).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 30, Issue 4, Pages 463–469, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2016-0333.

Export Citation

©2017 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Rosella Tomanin, Litsa Karageorgos, Alessandra Zanetti, Moeenaldeen Al-Sayed, Mitch Bailey, Nicole Miller, Hitoshi Sakuraba, and John J. Hopwood
Human Mutation, 2018

Comments (0)

Please log in or register to comment.
Log in