Orphanet Journal of Rare Diseases | Clinical and Genetic Characterization of 20 Chinese Patients with Congenital Disorders of Glycosylation

Recommend:

This study identified 28 pathogenic gene variants in 20 Chinese patients with congenital disorders of glycosylation (CDG), including 11 novel variants. It revealed genotype-phenotype correlations, offering new insights into the molecular mechanisms of CDG and providing a foundation for genetic counseling and diagnosis.

 

Literature Overview

The article titled 'Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients' was published in the 'Orphanet Journal of Rare Diseases'. It reviewed the clinical and genetic features of 20 Chinese CDG patients and identified multiple disease-causing genes, including ALG2, DPM2, PMM2, ALG13, etc. The pathogenicity of these variants was confirmed by Sanger sequencing and segregation analysis. Additionally, 11 novel variants were discovered, further expanding the genetic heterogeneity landscape of CDG.

Background Knowledge

Congenital disorders of glycosylation (CDG) are a group of inherited metabolic diseases caused by defects in glycosylation pathways, affecting N-linked, O-linked, and GPI-anchor glycosylation processes and resulting in multi-system dysfunction. CDG exhibits high clinical and genetic heterogeneity, with symptoms including developmental delay, epilepsy, hypotonia, liver dysfunction, facial dysmorphism, and perinatal death in severe cases, while milder forms may present in adulthood. Due to the rarity and clinical variability of CDG, patients often face delayed diagnosis and limited treatment options. This study represents the first systematic report of 20 CDG cases in China, covering multiple causative genes, highlighting the importance of genotype-phenotype correlations, and emphasizing the necessity of functional studies to uncover underlying pathogenic mechanisms.

 

Evaluates the pathogenic potential of genetic variants and provides a reference for functional analysis.

Learn More

 

Methods and Experiments

The research team conducted a retrospective analysis of 4912 patients suspected of having genetic disorders who underwent whole exome sequencing (WES) at Wuhan Children's Hospital between August 2018 and March 2025. Finally, 20 CDG patients were confirmed. WES was performed using IDT xGen Exome capture probes, followed by high-throughput sequencing on the Illumina NovaSeq 6000 platform. Variants were identified and annotated using tools such as GATK, BWA, and ANNOVAR. Variants with minor allele frequency (MAF < 0.01) in ExAC and gnomAD databases were filtered and analyzed for their impact on protein structure and function using bioinformatics tools like SIFT, PolyPhen-2, and MutationTaster. Variants were classified as pathogenic, likely pathogenic, or of uncertain significance according to the ACMG guidelines. Additionally, low-coverage whole-genome sequencing (CNV-seq) was used to detect large copy number variations (CNVs), and a mini gene splicing assay was performed to validate the impact of COG5 gene variants on splicing.

Key Findings and Insights

• 28 pathogenic variants were identified among the 20 CDG patients, 11 of which were novel and unreported in existing literature
• Variants in ALG2 before the transmembrane domain (N-terminal) are associated with CMS, whereas variants after the transmembrane domain (C-terminal) cause ALG2-CDG and are associated with more severe clinical phenotypes
• Variants in the first transmembrane domain of DPM2 (e.g., L59R) are associated with more severe phenotypes, with 3 patients carrying such variants dying before age 3
• Male hemizygous variants in SLC35A2 are associated with milder clinical manifestations compared to mosaic variants
• A novel pathogenic variant in SSR4 involving deletion of exons 4-6 was identified, presenting with developmental delay, language disorders, hypotonia, and mild facial dysmorphism
• The COG5 c.928 + 3A > G variant was confirmed to cause exon skipping via mini gene splicing assay, further supporting its pathogenicity
• 80% of patients follow autosomal recessive inheritance, and 20% follow X-linked inheritance, consistent with the overall genetic pattern of CDG
• Genotype-phenotype correlations were also observed, such as PMM2-CDG (CDG Ia) being common in this cohort, and ALG13-CDG (X-linked) primarily presenting with refractory epilepsy and neurodevelopmental delay

Significance and Future Directions

This study expands the variant spectrum and clinical phenotypes of CDG in the Chinese population and systematically summarizes genotype-phenotype correlations for multiple causative genes for the first time. Larger sample sizes and long-term follow-ups are needed to validate these observations and further explore the molecular mechanisms through functional studies. Glycan analysis technologies like MALDI-TOF MS should be integrated into the diagnostic workflow to improve the accuracy of variant pathogenicity assessment. Additionally, this study highlights the need to enhance CDG screening and genetic diagnostic capabilities in China to reduce diagnostic delays and optimize intervention strategies.

 

Compares genetic sequence differences between species or populations, suitable for evolutionary analysis.

Learn More

 

Conclusion

This study is the first systematic report of clinical and genetic characteristics of 20 CDG patients in the Chinese population, identifying 28 pathogenic variants, 11 of which are novel. It not only revealed genotype-phenotype correlations for multiple genes, such as ALG2, DPM2, and SLC35A2, but also validated the functional impact of COG5 variants through mini gene splicing assays. These findings provide new clues for studying the genetic mechanisms and clinical diagnosis of CDG, and highlight the necessity of further functional studies and large-scale population screening. In the future, integrating multi-omics analysis and international data sharing will help improve the precision of CDG diagnosis and treatment.

 

Peiwei Zhao, Li Tan, Qingjie Meng, Shiqiong Zhou, and Xuelian He. Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients. Orphanet Journal of Rare Diseases.