Clinical and genetic characterization of Congenital disorders of glycosylation in 20 Chinese patients: novel variants and genotype-phenotype correlations

Background: Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. These disorders can affect multiple organs, leading to a broad spectrum of symptoms that vary among different CDG subtypes and between individuals with same type of CDG. This study aimed to investigate the genetic variants, molecular etiologies, and clinical features of 20 Chinese patients diagnosed with CDG. Results: Using whole-exome sequencing (WES), functional prediction tools, Sanger sequencing, and segregation analysis, we identified variants in several genes: ALG2 (3 patients), DPM2 (3 patients), PMM2(3 patients), and ALG13 (2 patients). Additionally, variants in COG5, COG6, MOGS, DPM3, ALG1, ALG3, ALG11, SSR4 and SLC35A2 each were observed in single case. In total, 28 distinct variants were identified, 11 of which were previously unreported. Genotype-phenotype correlations revealed notable findings: variants in the N-terminus of ALG2 before the intramembrane domain were associated with congenital myasthenic syndromes (CMS), whereas those in the C-terminus caused ALG2-CDG; DPM2-CDG patients with variants in transmembrane region 1 exhibited more severe phenotypes; male patients with hemizygous variants in SLC35A2 demonstratedmilder phenotypes compared to those with mosaic variants. Conclusions: This findings expand the spectrum of known clinical presentations and genetic variants in CDG, and establish possible genotype-phenotype correlations of several pathogenic genes, emphasizing the need for functional studies to unravel the underlying mechanisms.