DOCK6Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

Abstract

Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.

CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis

“…Although no cardiovascular malformations were observed in the identified AOS patients carrying heterozygous gain-of-function mutations in the CdGAP gene333446, our results demonstrate here that the complete loss of CdGAP expression in mouse embryos leads to hypovascularization, vascular defects and incomplete embryonic/perinatal lethality. Interestingly, mutations in the DOCK6 gene encoding a Rac1/Cdc42 guanine nucleotide exchange factor responsible for an autosomal-recessive variant of AOS were recently associated with impaired vascular functions, supporting the importance of Rac1/Cdc42 signaling processes in vascular development4547. Furthermore, mutations in several genes of the Notch signaling pathway, including EOGT, RBPJ, Notch, and the Notch ligand Dll4, that encode important regulators of vascular development484950 were recently identified in AOS patients51525354.…”

“…Recently, mutations in the CdGAP gene have been identified in families of patients with autosomal dominant AOS33344445. AOS is a heterogeneous disorder, typically characterized by the presence of both aplasia cutis congenita of the scalp vertex and terminal limb defects3536.…”

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

“…7,8 In contrast, cerebral and ocular abnormalities, which have been found to be particularly associated with autosomal-recessive DOCK6-related AOS, appear to be uncommon in those autosomal-dominant forms. 24 In conclusion, through screening a cohort of 91 families affected with AOS or ACC, we have identified nine heterozygous variants in DLL4, including nonsense, cysteinereplacing or -creating, and other missense mutations, demonstrating that mutations in this gene are an important cause of autosomal-dominant AOS or isolated ACC. Affected individuals show variable clinical expression with no clear genotype-phenotype correlations at present.…”

Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system

“…An autosomal-recessive form of AOS was also found to be dependent on DOCK6, a guanine nucleotide exchange factor for Cdc42 and Rac1, two members of the Rho GTPase family Shaheen et al, 2011;Sukalo et al, 2015). In addition, autosomal dominant mutations for Notch1, RBPJ, and ARHGAP31…”

“…These neurological abnormalities appear to be associated with neurodevelopmental defects but could also be attributable to disruptive vasculogenesis. Indeed, some patients with AOS caused by DOCK6, Notch1, or EOGT mutations exhibited vascular defects in the brain (Cohen et al, 2014;Shaheen et al, 2013;Stittrich et al, 2014;Sukalo et al, 2015).…”