A Mild Form of Mucopolysaccharidosis IIIB Diagnosed with Targeted Next-generation Sequencing of Linked Genomic Regions

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2011 Jun 30

PMID 21712855

Citations 12

Authors

Kaja K Selmer

Gregor D Gilfillan

Petter Stromme

Robert Lyle

Timothy Hughes

Hanne S Hjorthaug

Kristin Brandal

Sigve Nakken

Doriana Misceo

Thore Egeland

Ludvig A Munthe

Sigrun K Braekken

Dag E Undlien

Affiliations

Soon will be listed here.

Abstract

Next-generation sequencing (NGS) techniques have already shown their potential in the identification of mutations underlying rare inherited disorders. We report here the application of linkage analysis in combination with targeted DNA capture and NGS to a Norwegian family affected by an undiagnosed mental retardation disorder with an autosomal recessive inheritance pattern. Linkage analysis identified two loci on chromosomes 9 and 17 which were subject to target enrichment by hybridization to a custom microarray. NGS achieved 20-fold or greater sequence coverage of 83% of all protein-coding exons in the target regions. This led to the identification of compound heterozygous mutations in NAGLU, compatible with the diagnosis of Mucopolysaccharidosis IIIB (MPS IIIB or Sanfilippo Syndrome type B). This diagnosis was confirmed by demonstrating elevated levels of heparan sulphate in urine and low activity of α-N-acetyl-glucosaminidase in cultured fibroblasts. Our findings describe a mild form of MPS IIIB and illustrate the diagnostic potential of targeted NGS in Mendelian disease with unknown aetiology.

Citing Articles

Early-onset motor polyneuropathy associated with a novel dominant NAGLU mutation.

Lopergolo D, Salvatore S, Sorrentino V, Malandrini A, Santorelli F, Battisti C Neurol Sci. 2023; 44(4):1415-1418.

PMID: 36648562 DOI: 10.1007/s10072-023-06607-0.

Sanfilippo syndrome: consensus guidelines for clinical care.

Muschol N, Giugliani R, Jones S, Muenzer J, Smith N, Whitley C Orphanet J Rare Dis. 2022; 17(1):391.

PMID: 36303195 PMC: 9612603. DOI: 10.1186/s13023-022-02484-6.

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants.

Encarnacao M, Coutinho M, Silva L, Ribeiro D, Ouesleti S, Campos T Int J Mol Sci. 2020; 21(17).

PMID: 32883051 PMC: 7503609. DOI: 10.3390/ijms21176355.

Diagnosis of Mucopolysaccharidoses.

Kubaski F, de Oliveira Poswar F, Michelin-Tirelli K, Burin M, Rojas-Malaga D, Brusius-Facchin A Diagnostics (Basel). 2020; 10(3).

PMID: 32235807 PMC: 7151013. DOI: 10.3390/diagnostics10030172.

Molecular Characterization of a Novel Splicing Mutation underlying Mucopolysaccharidosis (MPS) type VI-Indirect Proof of Principle on Its Pathogenicity.

Coutinho M, Encarnacao M, Matos L, Silva L, Ribeiro D, Santos J Diagnostics (Basel). 2020; 10(2).

PMID: 31973102 PMC: 7168280. DOI: 10.3390/diagnostics10020058.

References

Sobreira N, Cirulli E, Avramopoulos D, Wohler E, Oswald G, Stevens E . Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010; 6(6):e1000991. PMC: 2887469. DOI: 10.1371/journal.pgen.1000991. View

Choi M, Scholl U, Ji W, Liu T, Tikhonova I, Zumbo P . Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009; 106(45):19096-101. PMC: 2768590. DOI: 10.1073/pnas.0910672106. View

Yogalingam G, Hopwood J . Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat. 2001; 18(4):264-81. DOI: 10.1002/humu.1189. View

Volpi L, Roversi G, Colombo E, Leijsten N, Concolino D, Calabria A . Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene. Am J Hum Genet. 2009; 86(1):72-6. PMC: 2801743. DOI: 10.1016/j.ajhg.2009.11.014. View

Lupski J, Reid J, Gonzaga-Jauregui C, Rio Deiros D, Chen D, Nazareth L . Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010; 362(13):1181-91. PMC: 4036802. DOI: 10.1056/NEJMoa0908094. View

Zhao H, Li H, Bach G, Schmidtchen A, Neufeld E . The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci U S A. 1996; 93(12):6101-5. PMC: 39196. DOI: 10.1073/pnas.93.12.6101. View

Matsuzaki H, Loi H, Dong S, Tsai Y, Fang J, Law J . Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res. 2004; 14(3):414-25. PMC: 353229. DOI: 10.1101/gr.2014904. View

Bunge S, Knigge A, Steglich C, Kleijer W, van Diggelen O, Beck M . Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel alpha-N-acetylglucosaminidase gene mutations. J Med Genet. 1999; 36(1):28-31. PMC: 1762943. View

Valstar M, Bruggenwirth H, Olmer R, Wevers R, Verheijen F, Poorthuis B . Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J Inherit Metab Dis. 2010; 33(6):759-67. PMC: 2992652. DOI: 10.1007/s10545-010-9199-y. View

10.

Li H, Ruan J, Durbin R . Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008; 18(11):1851-8. PMC: 2577856. DOI: 10.1101/gr.078212.108. View

11.

Goren A, Ozsolak F, Shoresh N, Ku M, Adli M, Hart C . Chromatin profiling by directly sequencing small quantities of immunoprecipitated DNA. Nat Methods. 2009; 7(1):47-9. PMC: 2862482. DOI: 10.1038/nmeth.1404. View

12.

Valstar M, Ruijter G, van Diggelen O, Poorthuis B, Wijburg F . Sanfilippo syndrome: a mini-review. J Inherit Metab Dis. 2008; 31(2):240-52. DOI: 10.1007/s10545-008-0838-5. View

13.

Ng S, Bigham A, Buckingham K, Hannibal M, McMillin M, Gildersleeve H . Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010; 42(9):790-3. PMC: 2930028. DOI: 10.1038/ng.646. View

14.

Hoppman-Chaney N, Peterson L, Klee E, Middha S, Courteau L, Ferber M . Evaluation of oligonucleotide sequence capture arrays and comparison of next-generation sequencing platforms for use in molecular diagnostics. Clin Chem. 2010; 56(8):1297-306. DOI: 10.1373/clinchem.2010.145441. View

15.

Liu W, Di X, Yang G, Matsuzaki H, Huang J, Mei R . Algorithms for large-scale genotyping microarrays. Bioinformatics. 2003; 19(18):2397-403. DOI: 10.1093/bioinformatics/btg332. View

16.

Cooper D, Chen J, Ball E, Howells K, Mort M, Phillips A . Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum Mutat. 2010; 31(6):631-55. DOI: 10.1002/humu.21260. View

17.

Ficko-Blean E, Stubbs K, Nemirovsky O, Vocadlo D, Boraston A . Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB. Proc Natl Acad Sci U S A. 2008; 105(18):6560-5. PMC: 2373330. DOI: 10.1073/pnas.0711491105. View

18.

Wigginton J, Abecasis G . PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics. 2005; 21(16):3445-7. DOI: 10.1093/bioinformatics/bti529. View

19.

Abecasis G, Cherny S, Cookson W, Cardon L . Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2001; 30(1):97-101. DOI: 10.1038/ng786. View

20.

Zhao H, Aronovich E, Whitley C . Genotype-phenotype correspondence in Sanfilippo syndrome type B. Am J Hum Genet. 1998; 62(1):53-63. PMC: 1376807. DOI: 10.1086/301682. View