Genotype-Phenotype Association for 14 GFAP Variants in Alexander Disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Alexander disease is a rare, monogenic disorder linked to dominant variants in the glial fibrillary acidic protein (GFAP) gene.
• Over 180 GFAP variants are known, presenting a wide spectrum of disease severity and clinical features.
• Previous genotype-phenotype correlation attempts were limited by small case numbers for many variants.

Purpose of the Study:

• To investigate and establish genotype-phenotype correlations in Alexander disease.
• To determine if statistical analysis of available case data can reveal relationships between GFAP variants and disease characteristics.

Main Methods:

• Compiled a dataset of GFAP variants with at least 7 reported unrelated cases, including data from publications and natural history studies.
• Collected data on age at onset, age at death/last contact, and sex for each case.
• Utilized Kruskal-Wallis tests for age at onset comparisons and Kaplan-Meier curves for survival analysis.

Main Results:

• Analyzed 14 GFAP variants from 231 cases, identifying 3 distinct groups based on onset patterns: consistent early, consistent late, and variable.
• Found statistically significant differences in onset age between certain variants, e.g., R239H versus R239C.
• Observed similar groupings for survival patterns and found no significant impact of sex on onset or survival.

Conclusions:

• Genotype-phenotype correlations are evident in Alexander disease for specific GFAP variants.
• Sufficient case numbers are crucial for valid statistical analysis and establishing these correlations.
• This study provides a foundation for understanding variant-specific disease trajectories in Alexander disease.