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

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The ALG13 gene is associated with congenital disorders of glycosylation (CDG) and developmental and epileptic encephalopathy (DEE).
• Understanding the precise genotype-phenotype correlations for ALG13 variants is crucial but remains incomplete.

Purpose of the Study:

• To investigate the phenotypic spectrum associated with ALG13 variants.
• To explore genotype-phenotype correlations in patients with ALG13 mutations.
• To examine ALG13 expression patterns in neural organoid models.

Main Methods:

• Whole-exome sequencing (WES) was utilized to identify ALG13 variants in unrelated families.
• A systematic review of existing patient data for ALG13 variants was conducted.
• ALG13 expression patterns were analyzed using human organoid models.

Main Results:

• Five patients with ALG13 variants, including two novel ones, were identified.
• Epilepsy with neurodevelopmental impairment (including infantile epileptic spasms syndrome) was observed in four patients; one had developmental delay without seizures.
• Variants linked to isolated developmental delay were outside the glycosylation domain, while infantile-onset, treatment-refractory epilepsy predominated in DEE cases. Highest ALG13 expression occurred in ectodermal-derived neurons and later in deep-layer cortical neurons.

Conclusions:

• ALG13 variants present a wide phenotypic range, from DEE to non-epileptic neurodevelopmental impairment.
• Findings suggest a potential domain-specific genotype-phenotype association for ALG13.
• Further functional studies are needed to elucidate the pathogenic mechanisms of various ALG13 variants in neurodevelopmental disorders.