Homozygous variants in CDK5RAP2 were first reported individuals with microcephaly in consanguineous family in 2005 (Bond J, et al., PMID: 15793586). Primary microcephaly (OMIM:604804) characterized by a disproportionately small brain and cerebral cortex further characterized by other significant neurological deficits (delayed psychomotor development, moderate learning difficulties, and significant speech delay). Other clinical manifestation as variation were reported: severe sensorineural hearing loss (Pagnamenta et al. (2012), short stature (-6.7 SD), prominent eyes, conical-shaped and widely spaced teeth (Lancaster et al. (2013)). The mechanism of pathogenicity is known to be autosomal recessive loss-of-function. At least nine loss-of-function variants, 3 homozygous and 6 compound heterozygous, have been reported in 6 probands with primary microcephaly, 3 across six publications (PMIDs: 17764569, 15793586, 22887808, 27761245, 23726037, 23995685). This gene-disease relationship is also supported by patient-derived cerebral organoid (PMID: 23995685) and phenotypically compatible mouse model (PMIDs: 20460369). Inducing wildtype CDK5RAP2 expression rescued the developmental abnormality in patient-derived cerebral organoid, which is genetically knock-out for CDK5RAP2 (PMID: 23995685). In summary, CDK5RAP2 is definitively associated with autosomal recessive primary microcephaly, 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This was discussed and approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 01/25/2022 (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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