A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions

Eur J Hum Genet. 2012 Jan;20(1):58-63. doi: 10.1038/ejhg.2011.126. Epub 2011 Jun 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosaminidase / metabolism
  • Cells, Cultured
  • Chromosomes, Human, Pair 17 / genetics
  • Chromosomes, Human, Pair 9 / genetics
  • DNA Mutational Analysis / methods*
  • Female
  • Fibroblasts / metabolism
  • Genetic Linkage
  • Genetic Loci
  • Genome, Human
  • Heparitin Sulfate / urine
  • Humans
  • Inheritance Patterns
  • Male
  • Mental Disorders / diagnosis
  • Mental Disorders / genetics
  • Mental Disorders / metabolism
  • Middle Aged
  • Mucopolysaccharidosis III / diagnosis*
  • Mucopolysaccharidosis III / genetics
  • Mucopolysaccharidosis III / metabolism
  • Mutation
  • Norway
  • Oligonucleotide Array Sequence Analysis / methods*
  • Pedigree


  • Heparitin Sulfate
  • alpha-N-acetyl-D-glucosaminidase
  • Acetylglucosaminidase