*DCHS1 *was first reported in relation to autosomal recessive entities van Maldergem syndrome in 1992 (van Maldergem PMID: 1633641). At least three variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, experimental data.
Variants in *DCHS1 *have been reported in individuals with van Maldergem syndrome (OMIM: 601390) and mitral valve prolapse 2 (OMIM:607829). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in inheritance pattern and phenotypic variability. Therefore, van Maldergen syndrome (OMIM: 601390) and mitral valve prolapse 2 (OMIM:607829) have been split into different disease entities. The Brain Malformations GCEP performed curation for van Maldergem syndrome (OMIM: 601390) only.
Three variants (2 LoF, 1 missense) in this gene have been reported in at least 3 probands in 2 publications (PMID: 24056717, 22473091). Variants in this gene segregated with disease in 0 additional family members. This gene-disease relationship is supported by shRNA knockdown (electroporation) of DCHS1 in developing mouse brain at E13, evaluated E16-18 or P7 (PMID: 21303848). Treated animals developed cerebral development abnormalities, significant reduction of proliferating cells reaching the cortical plate. At P7, cells fail to migrate, accumulated below the gray matter forming region of neuronal heterotopia. This phenotype corresponds to neuronal heterotopia seen on patient brain MRI imaging.
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 6/11/2024.
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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