DDOST-Congenital Disorder of Glycosylation: Defining the Clinical Spectrum and First Report of a Structural Variant

Congenital disorders of glycosylation (CDG) are a heterogeneous group of metabolic diseases caused by defects in glycan biosynthesis, predominantly affecting the N-glycosylation pathway. Pathogenic variants in the DDOST gene, encoding a non-catalytic subunit of the oligosaccharyltransferase (OST) complex, underlie an ultra-rare CDG subtype with only three patients reported to date, complicating diagnosis and genotype-phenotype correlations. We describe a female patient with developmental delay, hypotonia, and dysmorphic features. Genetic analyses included chromosomal microarray, FMR1 testing, and trio-based next-generation sequencing with a neurodevelopmental disorder panel. Variants were assessed using ACMG criteria, population databases, segregation, and in silico analysis. We also reviewed published DDOST-CDG cases to compare clinical and molecular findings. Compound heterozygous DDOST variants were identified: (i) a maternally inherited 413-kb deletion encompassing exons 3-11, predicted to abolish gene function, and (ii) a paternally inherited in-frame deletion (p.Lys435del), removing a highly conserved residue in the luminal C-terminal domain. Both were absent from population databases and classified as pathogenic or likely pathogenic, consistent with autosomal recessive inheritance. Metabolic testing confirmed a type I transferrin isoform pattern, supporting a congenital disorder of glycosylation. This report expands the genetic and phenotypic spectrum of DDOST-CDG by describing the first structural variant. Review of published cases highlights hypotonia and motor delay as consistent features, while other traits such as strabismus, feeding difficulties, or hepatic dysfunction appear variable. Our findings underscore the clinical heterogeneity of DDOST-CDG and the complementary role of metabolic and genomic testing.