Clinical and molecular diagnosis of non‐phosphomannomutase 2 N‐linked congenital disorders of glycosylation in Spain

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non‐specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)‐CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non‐PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG‐I and 7 as CDG‐II. Pathogenic variations were found in 16 genes ( ALG1 , ALG6 , ATP6V0A2 , B4GALT1 , CCDC115 , COG7 , DOLK , DPAGT1 , DPM1 , GFPT1 , MPI , PGM1 , RFT1 , SLC35A2 , SRD5A3 , and SSR4 ). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.