These data demonstrate that the assignment of mutations to isoform groups was able to explain greater percentages of the variance in FSIQ than consideration of the effects of mutations purely by location, and underscores the importance of the functional consequences of mutation location as underlying some of the liability of cognitive disability in DMD.
Model 5 explained a greater percentage of the variance in FSIQ than the other alternative two group models based on assignment of mutations to DMD isoforms, and also accounted for more of the variance than 2 group models based on the physical location of mutations proximal of exon 30 (F = 10.44; p = 0.002) or exon 45 (F = 12.82; p = 0.0007).
Secondly, the existence of numerous human haplogroups further complicates the correct assignment of mutations, as the penetrance of some variants might change in different genetic contexts (22).
The.out file produced by this latter program was manipulated in a spreadsheet to directly obtain the assignment of mutations to each of the tree branches.
These two assumptions are translated into the EXPANDS model in four main steps: cell frequency estimation, clustering, filtering and assignment of mutations to clusters (Fig. 1).
The low scores of the R147W, R199P and A341V variants underscore the need to question the assignment of these mutations as pathogenic.
Assignment of a specific mutation as a true predisposition to a disease family requires solid phenotypic evidence from in vitro analysis, cell line tests, search of the literature, bioinformatics data analysis, and animal models.
Because the assignment of genes to mutations is done based on co-occurrences, sometimes a mutation is assigned to several genes.
Complementation tests allowed assignment of the 45 mutations to 24 loci.
Finally, results using exogenously added δ-aminolevulinic acid (ALA), a heme precursor that increases the levels of endogenous heme available for heme proteins, supported the functional assignments of certain mutations involved in heme binding.
