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Background <p>Lysosomal storage diseases (LSDs) are a group of genetically heterogeneous inherited metabolic disorders that affect the functions of the lysosomes in different human tissues. Mucopolysaccharidosis IIIB (MPS IIIB), Sanfilippo B syndrome, is an autosomal recessive LSD characterized by a deficiency of the lysosomal enzyme α-N-acetylglucosaminidase. This study aims to investigate the molecular genetic spectrum of α-N-acetyl-glucosaminidase (<i>NAGLU</i>) variants, as well as their biochemical and clinical characteristics, in a cohort of MPS IIIB Egyptian patients. This study aims to expand the characterization of biochemical and molecular spectrum profiles of MPSIIIB in Egyptian patients since this monogenic disease seems commonly encountered in our population.</p> Patients and methods <p>A cohort of eleven children from unrelated Egyptian families, clinically and biochemically diagnosed with MPS IIIB based on heparan sulphate accumulation, were enrolled in the present study. Patients variably presented with early-onset, progressive neurological and mental deterioration, aggressive and hyperactive behaviors, sleep disturbances, and hepatosplenomegaly. Bayesian Gaussian Mixture machine learning (ML) model, an in-silico prediction tool, protein modelling, and thermodynamic stability predictions were applied to assess the functional consequences, and the potential clinical impact of two missense variants, recently reported .</p> Results&#xa0; <p>Sanger sequencing of the <i>NAGLU</i> coding and exon-intron boundaries revealed seven different homozygous disease-causing variants [p.(Leu348Arg), p.(Val117Leu), p.(Trp268Arg), p.(Glu452Lys), p.(Arg482Trp), p.(Arg482Gln), and p.(Leu550Pro)] The most frequently encountered variant was the p.(Arg482Trp) (12/22; 37%) located in exon 6, followed by the missense variant p.(Trp268Arg) (4/22; 18%) in exon 5, while the other three missense variants, p.(Glu452Lys), p.(Arg482Gln), and p.(Leu550Pro)] each appeared in only one patient, representing 9% of the disease-causing variants. Sixteen mutant alleles (16/22; 72%) were identified in <i>NAGLU</i> exon 6, indicating that exon 6 is a hotspot in Egyptian Sanfilippo B patients. In silico analysis using multiple computational tools and the Bayesian Gaussian Mixture ML model for assessment of missense variants predicted the p.(Leu348Arg) missense variant to be deleterious and destabilizing the protein structure. In contrast, the p.(Val117Leu) missense variant was consistently predicted to have a stabilizing effect on the protein.</p> Conclusions <p>This study expands the molecular genetic spectrum of the <i>NAGLU</i> mutations associated with MPS IIIB in Egyptian patients. The study results highlight exon 6 as a hot-spot for the first screening of <i>NAGLU</i> gene in Egyptian families with MPS IIIB. This will promote the early diagnosis and genetic counselling for patients and their families in Egypt. The application of a machine learning (ML) model to assess missense variants identified in our Egyptian patients provided significant insights into their clinical impact and the observed variable clinical severity. The use of AMCMG criteria and in silico tools to predict the pathogenicity and protein stability changes of these variants proved valuable and demonstrated the utility of computational methods in assessing the clinical relevance of genetic variants.</p>

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Clinical, biochemical, and molecular characterization of a cohort of Egyptian patients with Sanfilippo B syndrome (MPS IIIB): Bayesian Gaussian mixture model

  • 期刊论文

  • 发表日期：

    2025年10月10日

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  • Ekram Fateen,
  • Soha S. Nosier,
  • Amira M. Radwan,
  • Eman E. A. Mohammed

摘要

Background

Lysosomal storage diseases (LSDs) are a group of genetically heterogeneous inherited metabolic disorders that affect the functions of the lysosomes in different human tissues. Mucopolysaccharidosis IIIB (MPS IIIB), Sanfilippo B syndrome, is an autosomal recessive LSD characterized by a deficiency of the lysosomal enzyme α-N-acetylglucosaminidase. This study aims to investigate the molecular genetic spectrum of α-N-acetyl-glucosaminidase (NAGLU) variants, as well as their biochemical and clinical characteristics, in a cohort of MPS IIIB Egyptian patients. This study aims to expand the characterization of biochemical and molecular spectrum profiles of MPSIIIB in Egyptian patients since this monogenic disease seems commonly encountered in our population.

Patients and methods

A cohort of eleven children from unrelated Egyptian families, clinically and biochemically diagnosed with MPS IIIB based on heparan sulphate accumulation, were enrolled in the present study. Patients variably presented with early-onset, progressive neurological and mental deterioration, aggressive and hyperactive behaviors, sleep disturbances, and hepatosplenomegaly. Bayesian Gaussian Mixture machine learning (ML) model, an in-silico prediction tool, protein modelling, and thermodynamic stability predictions were applied to assess the functional consequences, and the potential clinical impact of two missense variants, recently reported .

Results 

Sanger sequencing of the NAGLU coding and exon-intron boundaries revealed seven different homozygous disease-causing variants [p.(Leu348Arg), p.(Val117Leu), p.(Trp268Arg), p.(Glu452Lys), p.(Arg482Trp), p.(Arg482Gln), and p.(Leu550Pro)] The most frequently encountered variant was the p.(Arg482Trp) (12/22; 37%) located in exon 6, followed by the missense variant p.(Trp268Arg) (4/22; 18%) in exon 5, while the other three missense variants, p.(Glu452Lys), p.(Arg482Gln), and p.(Leu550Pro)] each appeared in only one patient, representing 9% of the disease-causing variants. Sixteen mutant alleles (16/22; 72%) were identified in NAGLU exon 6, indicating that exon 6 is a hotspot in Egyptian Sanfilippo B patients. In silico analysis using multiple computational tools and the Bayesian Gaussian Mixture ML model for assessment of missense variants predicted the p.(Leu348Arg) missense variant to be deleterious and destabilizing the protein structure. In contrast, the p.(Val117Leu) missense variant was consistently predicted to have a stabilizing effect on the protein.

Conclusions

This study expands the molecular genetic spectrum of the NAGLU mutations associated with MPS IIIB in Egyptian patients. The study results highlight exon 6 as a hot-spot for the first screening of NAGLU gene in Egyptian families with MPS IIIB. This will promote the early diagnosis and genetic counselling for patients and their families in Egypt. The application of a machine learning (ML) model to assess missense variants identified in our Egyptian patients provided significant insights into their clinical impact and the observed variable clinical severity. The use of AMCMG criteria and in silico tools to predict the pathogenicity and protein stability changes of these variants proved valuable and demonstrated the utility of computational methods in assessing the clinical relevance of genetic variants.