Genotype-Phenotype Association for 14

Background and Objectives: Alexander disease is a rare monogenic disorder caused by dominant variants in Methods: We compiled a list of variants in Results: Fourteen variants met our criteria for detailed analysis (10 with 7 or more unrelated cases and 4 additional variants involving 2 of the most commonly affected amino acids, R79 and R239) derived from a total of 231 cases. The variants seem to fall into 3 distinct groups-some with consistent early onsets (N77S, R79C and R79L, and most of the R239s), some with consistent late onsets (R70W and N386S), and some with more variable onsets (R416W). Pairwise comparison results found that R239H was associated with significantly earlier onsets than R239C. We found similar groupings for survival. Finally, we evaluated sex as a potential modifying factor for either age at onset or survival but found no significant association. Discussion: Genotype-phenotype correlations do exist in Alexander disease, at least for a limited number of GFAP variants for which sufficient numbers of individual cases can be identified to allow valid statistical analysis.