Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

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.