Variants in MCPH1 were first reported in relation to autosomal recessive microcephaly with intellectual disability in 2010 (PMID: 20978018). Probands are characterized by microcephaly with mild to moderate intellectual disability or developmental delay, and dysmorphic features including up-slanting palpebral fissure and broad tip nose (PMIDs: 22855649, 25870538, 20978018). Nineteen unique homozygous or compound loss-of-function variants, reported in multiple unrelated probands, in five publications, are included in this curation (PMIDs: 20978018, 25870538, 22855649, 35281599, 35456400). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism for the disease is reported as haploinsufficiency. Currently, the gene-disease relationship is not supported by experimental evidence. Mouse models recapitulating microcephaly are described but were not scored as no developmental delay phenotype was described (PMID: 33542216).
In summary, there is definitive evidence to support the relationship between MCPH1 and autosomal recessive microcephaly with intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 17, 2023 (SOP 9).
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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