Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB
-
Qingwen Zeng
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.
Acknowledgments
We are grateful to the patient and his family members for their participation in this study. We also express our gratitude to all of the pediatricians who helped with the study.
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.
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;93:6101–5.10.1073/pnas.93.12.6101Search in Google Scholar
2. Hara A, Kitazawa N, Taketomi T. Abnormalities of glycosphingolipids in mucopolysaccharidosis type III B. J Lipid Res 1984;25:175–84.10.1016/S0022-2275(20)37837-8Search in Google Scholar
3. Haust MD, Gordon BA. Ultrastructural and biochemical aspects of the Sanfilippo syndrome – type III genetic mucopolysaccharidosis. Connect Tissue Res 1986;15:57–64.10.3109/03008208609001973Search in Google Scholar PubMed
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.Search in Google Scholar
5. Valstar MJ, Ruijter GJ, van Diggelen OP, Poorthuis BJ, Wijburg FA. Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31:240–52.10.1007/s10545-008-0838-5Search in Google Scholar PubMed
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;31:631–55.10.1002/humu.21260Search in Google Scholar PubMed
7. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010;26:589–95.10.1093/bioinformatics/btp698Search in Google Scholar PubMed PubMed Central
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;25:2283–5.10.1093/bioinformatics/btp373Search in Google Scholar PubMed PubMed Central
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;43:491–8.10.1038/ng.806Search in Google Scholar PubMed PubMed Central
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;20:1297–303.10.1101/gr.107524.110Search in Google Scholar PubMed PubMed Central
11. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.10.1093/nar/gkq603Search in Google Scholar PubMed PubMed Central
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.Search in Google Scholar
13. Zhao HG, Aronovich EL, Whitley CB. Genotype-phenotype correspondence in Sanfilippo syndrome type B. Am J Hum Genet 1998;62:53–63.10.1086/301682Search in Google Scholar PubMed PubMed Central
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;33:759–67.10.1007/s10545-010-9199-ySearch in Google Scholar PubMed PubMed Central
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;18:873–80.10.1038/mt.2010.17Search in Google Scholar PubMed PubMed Central
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;5:42–9.10.1006/mthe.2001.0514Search in Google Scholar PubMed
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;4:118ra10.10.1126/scitranslmed.3003310Search in Google Scholar PubMed PubMed Central
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;4:138ra78.10.1126/scitranslmed.3003544Search in Google Scholar PubMed PubMed Central
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;49:353–61.10.1136/jmedgenet-2012-100819Search in Google Scholar PubMed PubMed Central
©2017 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Pediatric endocrinology is pediatrics is public health
- Original Articles
- Total body fat, abdominal fat, body fat distribution and surrogate markers for health related to adipocyte fatty acid-binding protein (FABP4) in children
- Vitamin D supplementation, the metabolic syndrome and oxidative stress in obese children
- Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control
- Cross-sectional analysis of universal vitamin D supplementation in former East Germany during the first year of life
- Ethnicity and incidence of congenital hypothyroidism in the capital of Macedonia
- Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy
- Leptin and adiponectin levels in discordant dichorionic twins at 72 hours of age-associations with anthropometric parameters and insulin resistance
- Analysis of growth hormone receptor gene expression in tall and short stature children
- Clinical features of girls with short stature among inv (9), Turner (45, X) and control individuals
- Hereditary vitamin D-resistant rickets in Lebanese patients: the p.R391S and p.H397P variants have different phenotypes
- Associations between obesity, adverse behavioral patterns and cardiovascular risk factors among adolescent inhabitants of a Greek island
- Increase of body mass index (BMI) from 1.5 to 3 years of age augments the degree of insulin resistance corresponding to BMI at 12 years of age
- Case Reports
- The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency
- Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB
- Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation
- Cushing’s syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma
- Letters to the Editor
- Growth-hormone deficiency in mitochondrial disorders
- Response to Growth hormone deficiency in mitochondrial disorders
Articles in the same Issue
- Frontmatter
- Editorial
- Pediatric endocrinology is pediatrics is public health
- Original Articles
- Total body fat, abdominal fat, body fat distribution and surrogate markers for health related to adipocyte fatty acid-binding protein (FABP4) in children
- Vitamin D supplementation, the metabolic syndrome and oxidative stress in obese children
- Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control
- Cross-sectional analysis of universal vitamin D supplementation in former East Germany during the first year of life
- Ethnicity and incidence of congenital hypothyroidism in the capital of Macedonia
- Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy
- Leptin and adiponectin levels in discordant dichorionic twins at 72 hours of age-associations with anthropometric parameters and insulin resistance
- Analysis of growth hormone receptor gene expression in tall and short stature children
- Clinical features of girls with short stature among inv (9), Turner (45, X) and control individuals
- Hereditary vitamin D-resistant rickets in Lebanese patients: the p.R391S and p.H397P variants have different phenotypes
- Associations between obesity, adverse behavioral patterns and cardiovascular risk factors among adolescent inhabitants of a Greek island
- Increase of body mass index (BMI) from 1.5 to 3 years of age augments the degree of insulin resistance corresponding to BMI at 12 years of age
- Case Reports
- The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency
- Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB
- Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation
- Cushing’s syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma
- Letters to the Editor
- Growth-hormone deficiency in mitochondrial disorders
- Response to Growth hormone deficiency in mitochondrial disorders
