Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG

Area of Science:

• Biochemistry
• Genetics
• Clinical Medicine

Background:

• PMM2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disorder.
• Understanding genotype/phenotype correlations is crucial for PMM2-CDG management.

Purpose of the Study:

• To analyze the largest dataset of PMM2-CDG patients.
• To identify novel PMM2 variants.
• To investigate genotype/phenotype and genotype/biochemical parameter correlations.

Main Methods:

• Collected genetic, clinical, and biochemical data from 137 PMM2-CDG patients.
• Classified PMM2 variants by predicted pathogenetic mechanism.
• Utilized Nijmegen Progression CDG Rating Scale (NPCRS) and biochemical assays.

Main Results:

• Identified 60 unique PMM2 variants, including six novel ones.
• Common variants include p.Arg141His, p.Pro113Leu, and p.Phe119Leu.
• Dysregulated coagulation factors (antithrombin, Factor XI, protein C) were consistently observed.
• Genotype/phenotype correlations revealed milder disease with p.Cys241Ser and severe disease with p.Val231Met, dimerization, and folding variants.

Conclusions:

• This study provides new insights into PMM2-CDG genetics and disease mechanisms.
• Larger sample size and inclusion of biochemical data enhance genotype/phenotype correlation understanding.
• Findings contribute to a better understanding of PMM2-CDG heterogeneity.