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.
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Acknowledgements
We thank Jan-Eric Månsson, Department of Neurochemistry, Sahlgren's University Hospital, Molndal, Sweden, for NAGLU enzyme assay, Berit Woldseth, Department of Medical Biochemistry, Oslo University Hospital, for thin layer chromatography, Knut Lindberg, Department of Ophthalmology, Oslo University Hospital for fundus photography, and Andres Server, Department of Radiology, Oslo University Hospital, for interpreting MRI images. The sequencing service was provided by the Norwegian High-Throughput Sequencing Centre, a national technology platform supported by the ‘Functional Genomics’ and ‘Infrastructure’ programs of the Research Council of Norway and the Southeastern Regional Health Authorities.
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Selmer, K., Gilfillan, G., Strømme, P. et al. A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions. Eur J Hum Genet 20, 58–63 (2012). https://doi.org/10.1038/ejhg.2011.126
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DOI: https://doi.org/10.1038/ejhg.2011.126
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