Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations

Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature. Elucidated genetic causes include four genes in different pathways, leading to a model of AOS as a multi-pathway disorder. We identified an infant with mild aplasia cutis congenita and terminal transverse limb defects, developmental delay and a severe, diffuse angiopathy with incomplete microvascularization. Whole-genome sequencing documented two rare truncating variants in DOCK6, a gene associated with a type of autosomal recessive AOS that recurrently features periventricular calcification and impaired neurodevelopment. We highlight an unexpectedly high frequency of likely deleterious mutations in this gene in the general population, relative to the rarity of the disease, and discuss possible explanations for this discrepancy.