A call for caution in expanding the mutational spectrum of SI gene deficiency

Genetic sucrase-isomaltase deficiency (GSID) is increasingly recognized as a potentially underdiagnosed cause of chronic gastrointestinal symptoms in both children and adults. Once considered a rare autosomal recessive disorder with early, severe presentation, it is now understood to encompass a broader clinical spectrum, including milder and later-onset phenotypes that may overlap with irritable bowel syndrome.

This commentary reviews recent advances in next-generation sequencing and current evidence on pathogenic SI gene variants, molecular mechanisms, genotype-phenotype relationships, and challenges in clinical interpretation.

Advances in genomic sequencing have facilitated increased identification of pathogenic SI variants associated with GSID. However, interpretation remains challenging due to variable penetrance and expressivity, with dominant-negative effects also considered possible. Additional challenges include inconsistent variant terminology, limited genotype-phenotype correlation, and heterogeneous functional data, all of which complicate diagnosis and prevalence estimation.

Careful molecular interpretation, structured clinical assessment, and standardized terminology are needed to improve diagnosis and guide management across the full spectrum of GSID severity.