Submission Details

DAO was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) in 2010 (Mitchell et al., PMID: 20368421). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, amyotrophic lateral sclerosis 1 (OMIM: 105400), schizophrenia (OMIM: 181500) and bipolar disorder (OMIM: 612371). The split curation for autosomal dominant ALS has been curated separately. The mechanism of pathogenicity appears to be loss of function. Four missense variants that have been reported in six probands in 4 publications (PMIDs: 20368421, 20538972, 29895397, 33414559) are included in this curation. This gene-disease association is also supported by animal models and functional alterations in primary rat motor neurons and non-patient cells (PMIDs: 20368421, 22203986, 29194436). Mouse animal models which express pathogenic and naturally inactivating DAO mutations recapitulate the ALS phenotype by displaying motor neuron loss and neuronal ubiquitin-positive aggregates. Furthermore, non-patient NSC-34 cells express higher amounts of apoptotic markers when co-cultured with glioma C6 cells expressing R199W. This is mediated by D-serine as confirmed by reduced levels of early and late apoptotic markers when NMDARs in NSC-34 cells are blocked with a D-serine/glycine binding site antagonist. In summary, DAO has limited association with autosomal dominant ALS. This classification was approved by the ClinGen ALS GCEP on March 8, 2022 (SOP Version 8).