ASPM was first reported in relation to autosomal recessive microcephaly in 2002 (Bond et al., PMID: 12355089). 10 variants (nonsense, frameshift) that have been reported in over 15 probands in 5 publications (PMIDs: 12355089, 15355437, 16141009, 18452193, 19332161) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, mouse model, and ferret model; PMIDs: 15972725, 20823249, 29643508). Expression analysis in human cells shows that ASPM is localized, along with chromosomal DNA, at the spindle poll during cell division. Both the mouse and ferret mutants recapitulate the human phenotype of microcephaly. In summary, there is definitive evidence supporting the relationship between ASPM and autosomal recessive microcephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 3/12/2024 (SOP Version 10).
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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