Whole-Exome sequencing and systems biology approaches revealed pathogenicity of compound heterozygote variants of NAGLU gene manifesting developmental regression, brain atrophy, intellectual disability, and ADHD.

backgroundSanfilippo syndrome type B results from NAGLU mutations which cause progressive cognitive impairments and central nervous system degeneration. A 10-year-old boy presented with developmental regression, brain atrophy, intellectual disability, attention-deficit/hyperactivity disorder, and restlessness. His parents were non-consanguineous and asymptomatic.

methodsWhole-exome sequencing (WES) was performed, and variants were confirmed by Sanger sequencing. Downstream analyses integrated protein-protein interaction (PPI), gene-microRNA interaction (GMI), and drug-disease association (DDA) networks using STRING, NetworkAnalyst, and Enrichr.

resultsTwo missense variants were identified including rs1358994052 (NAGLU:c.874G > A; p.Gly292Arg) and rs768918822 (NAGLU:c.1004 A > G; p.Tyr335Cys [Y335C]), classified as pathogenic and likely pathogenic, respectively, by ACMG guidelines. Both variants localize to regulatory elements. The compound heterozygote network exhibited increased PPI connectivity and the absence of hsa-miR-27a-3p in GMI analysis. DDA highlighted carcinogenesis as the top-ranked term in the compound heterozygote network, contrasting with leukemia associations in homozygous contexts.

conclusionCompound heterozygous regulatory variants in NAGLU underlie diverse biochemical and neurodevelopmental phenotypes beyond enzymatic deficiency, emphasizing the value of integrative WES and systems biology approaches to refine pathogenicity assessments and guide targeted functional validation.