CRBN was initially reported in relation to autosomal recessive intellectual disability (ID) in 2004 in a large consanguineous kindred (PMID: 15557513). Affected individuals presented with non-syndromic mild ID and were found to carry a homozygous nonsense variant. Two additional families have been reported. Five affected members of a consanguineous Saudi family with severe ID, self-mutilating behavior, and seizures carried a homozygous missense variant (PMID: 28143899). In a consanguineous family from Syria, 3 individuals with ID had a homozygous splice site variant (PMID: 28097321). There is experimental evidence to support this gene-disease relationship, including data showing that the Arg419* variant results in enhanced autoubiquitination and degradation (PMID: 23983124), and mouse models that exhibit learning, memory, and synaptic defects (PMIDs: 21995942, 29459374). In summary, there is moderate evidence supporting a relationship between CRBN and autosomal recessive ID. Given that only three families with pathogenic CRBN variants have been identified since the original report in 2004, additional genetic evidence is necessary to strengthen this gene-disease relationship. This curation was approved by the ClinGen ID/Autism Gene Curation Expert Panel on 2021 May 3 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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