Loss of Protocadherin ‐12 Leads to Diencephalic‐Mesencephalic Junction Dysplasia Syndrome

ObjectiveTo identify causes of the autosomal ‐recessive malformation, diencephalic‐mesencephalic junction dysplasia (DMJD) syndrome.MethodsEight families with DMJD were studied by whole ‐exome or targeted sequencing, with detailed clinical and radiological characterization. Patient‐derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.ResultsAll patients showed biallelic mutations in the nonclusteredprotocadherin ‐12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression ofPCDH12 in neural and endothelial cells. These cells showed lack ofPCDH12 expression and impaired neurite outgrowth.InterpretationDMJD patients have biallelic mutations inPCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated withPCDH12‐related conditions. Ann Neurol 2018

Source: Annals of Neurology - October 4, 2018 Category: Neurology Authors: Alicia Guemez ‐Gamboa, Ahmet Okay Çağlayan, Valentina Stanley, Anne Gregor, Maha S. Zaki, Sahar N. Saleem, Damir Musaev, Jennifer McEvoy‐Venneri, Denice Belandres, Naiara Akizu, Jennifer L. Silhavy, Jana Schroth, Rasim Ozgur Rosti, Bret Tags: Research Article Source Type: research