Novel ALG13 Variants and an Expanded Neurodevelopmental Spectrum: Genotype–Phenotype Correlations

Abstract

Background The ALG13 gene is implicated in congenital disorders of glycosylation (CDG) and developmental and epileptic encephalopathy (DEE), yet genotype–phenotype correlations remain incompletely understood. Methods Whole‐exome sequencing (WES) was performed in unrelated families, and we systematically reviewed existing patient data on ALG13 variants and investigated the expression patterns of ALG13 using organoid models. Results This study reports five patients with ALG13 variants, including two novel variants. Four patients presented with epilepsy accompanied by neurodevelopmental impairment, including infantile epileptic spasms syndrome (IESS) and drug‐resistant epilepsy, whereas one patient showed developmental delay without seizures. Further analysis revealed that variants identified in patients with isolated developmental delay were primarily located outside the key glycosylation functional domain. Statistical analysis of patients with epileptic encephalopathy showed that infantile‐onset seizures were the predominant feature, with most cases being refractory to treatment. Additionally, in organoids, the highest ALG13 expression was observed at 1 month in ectodermal‐derived neurons (EN). At 5 months, peak expression shifted to deep‐layer cortical neurons (EN‐CTX‐Deep). Conclusions ALG13 variants are associated with a broad phenotypic spectrum ranging from DEE to neurodevelopmental impairment without seizures. Our findings support a possible domain‐related genotype–phenotype association and provide additional developmental context for the role of ALG13 in neurodevelopmental disorders. Further functional studies are required to clarify the pathogenic mechanisms of different ALG13 variants.