title: A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions.
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.
authors.affiliation: Department and Institute of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Kaja K
authors.initials: KK
authors.lastname: Selmer
authors.forename: Gregor D
authors.initials: GD
authors.lastname: Gilfillan
authors.forename: Petter
authors.initials: P
authors.lastname: Strømme
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Timothy
authors.initials: T
authors.lastname: Hughes
authors.forename: Hanne S
authors.initials: HS
authors.lastname: Hjorthaug
authors.forename: Kristin
authors.initials: K
authors.lastname: Brandal
authors.forename: Sigve
authors.initials: S
authors.lastname: Nakken
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
authors.forename: Thore
authors.initials: T
authors.lastname: Egeland
authors.forename: Ludvig A
authors.initials: LA
authors.lastname: Munthe
authors.forename: Sigrun K
authors.initials: SK
authors.lastname: Braekken
authors.forename: Dag E
authors.initials: DE
authors.lastname: Undlien
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D056426:Genetic Loci; D015894:Genome, Human; D006497:Heparan Sulfate / Q000652:urine; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009084:Mucopolysaccharidosis III / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009664:Norway; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010375:Pedigree
chemical_list: D000118:Acetylglucosaminidase; D006497:Heparan Sulfate; C033079:alpha-N-acetyl-D-glucosaminidase