Different missense mutations in the PUM1 gene have been described. Some individuals with PADDAS have genomic deletions spanning the entire PUM1 gene.
The underlying pathophysiology of PUM1-related disorders is still being researched. PUM1 is an RNA-binding protein that regulates hundreds of mRNA targets in the brain. Loss of PUM1 function or lowering of the functional levels of PUM1 protein leads to deregulation of these targets. The PUM1 targetome is being mapped and ongoing research efforts are seeking to understand the specific genes and pathways responsible for different features of PUM1-associated conditions.
Testing for PUM1-related condition requires sequencing of the PUM1 gene either by traditional Sanger sequencing or a next-generation sequencing methodology (panel testing, exome or genome). As PADDAS can be caused by chromosomal deletions, a method of genetic testing that can look for whole or partial chromosomal deletions is also important, such as chromosomal microarray or MLPA (multiple ligation probe analysis). As most PUM1-variants to date are non-recurrent, more work may be required (for example testing of additional family members to segregate the disease, use of in silico tools to predict pathogenicity or molecular/functional studies) to build evidence that a detected variant is truly pathogenic. Repository of the variant and levels of evidence for causality in publically available international database is recommended in order to aid interpretation of novel variants.