Adams Oliver syndrome (AOS) was initially described in 1945 by F. H. Adams and C. P. Oliver as an autosomal dominant disorder clinically characterized by an absence of the lower extremities, digits and some of the metacarpals; and skin and skull lesions similar to those of aplasia cutis congenita. Variants inherited in autosomal recessive manner in DOCK6 gene were first reported in individuals with AOS in 2011 (Shaheen R. et al., PMID:21820096).
DOCK6 is a member of the conserved DOCK-C (dedicator of cytokinesis) subfamily and has crucial role on cytoskeletal organization. *DOCK6 *acts as a guanidine nucleotide exchange factor (GEF) for CDC42 and RAC1 proteins which belong to the Rho GTPase family.
Phenotypic variability has been reported in patients carrying pathogenic variants in DOCK6 gene with some patients exhibiting also seizures and ocular defects. The mechanism of pathogenicity is biparentally inherited loss-of-function variants. Nine frameshift variants were reported in 11 probands across eight publications (PMIDs: 21820096, 23522784, 25091416, 25824905, 29924900, 31654484, 32498638, 33655927), 7 splice site in 10 probands (PMIDs: 23522784, 25824905, 28884918, 29631299, 30898718, 31654484, 33655927), 5 nonsense variants in 6 probands (PMIDs: 25091416, 25824905, 28884918, 29924900, 29631299, 30898718), 4 missense in 4 probands (PMID: 25824905) and one intragene deletion including exons 42-47 in one proband (PMID: 25824905).
This gene-disease relationship is also supported by the observed defects in cytoskeletal organization in fibroblasts from an affected proband (PMID:21820096) and in vitro with the use of cell lines indicating the cytoskeletal and neurite defects after knockdown of DOCK6 (PMID:17196961).
In summary, DOCK6 is definitively associated with autosomal recessive Adams Oliver syndrome. This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on June 28, 2022 (SOP version 9).
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