Case Report: DGAT1 deficiency in three infants including a novel missense variant: structural insights and comparison...

DGAT1 deficiency is a rare cause of congenital diarrhea and protein-losing enteropathy, with only 39 reported cases and limited characterization of missense variants. This study integrates molecular interpretation with clinical data to refine genotype-phenotype correlations.

Three Palestinian infants with DGAT1 deficiency were analyzed, and a structured literature search was conducted. The diagnosis was established by whole-exome sequencing, with confirmatory Sanger sequencing. A novel variant underwent segregation testing, conservation assessment, and three-dimensional protein modeling using cryo-electron microscopy structures. All patients presented with congenital diarrhea, hypoalbuminemia, and severe growth faltering. Two known loss-of-function variants (c.1183C>T; p.Arg395Ter and c.895-1G>A) and one novel homozygous missense variant (c.820C>T; p.Arg274Trp) were identified. Structural modeling localized the residue to the substrate tunnel, where substitution of arginine with tryptophan is predicted to disrupt acyl-CoA entry into the catalytic chamber. Literature comparison suggests a partial residual function consistent with later presentation. All patients improved with low-fat, amino acid-based nutrition.

These findings expand the DGAT1 mutational spectrum and support the potential value of structure-informed analysis in the interpretation of rare missense variants, while highlighting the importance of early recognition and targeted nutritional therapy.