Submission Details

Variants in CRADD were initially reported in relation to autosomal recessive non-syndromic intellectual disability in 2012 in a Mennonite family with five individuals with developmental delay and intellectual disability (PMID: 22279524). Later, in 2016, variants in this gene were observed in individuals with lissencephaly and megalencephaly; this publication also reports MRI findings from the original Mennonite family reported in 2012, demonstrating that they also had lissencephaly (PMID: 27773430). Given the findings of developmental delay, intellectual disability, and lissencephaly, we chose to curate this gene for its relationship with autosomal recessive syndromic intellectual disability. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Biallelic frameshift, missense, and start-loss variants in CRADD have been reported in at least 47 probands in 6 publications (PMIDs: 22279524, 27773430, 28686357, 30167849, 33647455, 30914828); loss of function is the purported disease mechanism (PMIDs: 27773430, 28686357). Two founder variants have been identified in Mennonite and Finnish populations (PMIDs: 22279524, 27773430, 30914828). This gene-disease relationship is further supported by in vitro functional assays and a mouse model (PMID: 27773430). In summary,