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

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, Brett Copeland, Steven M. Lewis, Rebecca Fang, Mahmoud Y. Issa, Huseyin Per, Hakan Gumus, Ayse Kacar BayramSefer Kumandas, Gozde Tugce Akgumus, Emine Z. Erson-Omay, Katsuhito Yasuno, Kaya Bilguvar, Gali Heimer, Nir Pillar, Noam Shomron, Daphna Weissglas-Volkov, Yuval Porat, Yaron Einhorn, Stacey Gabriel, Bruria Ben-Zeev, Murat Gunel, Joseph G. Gleeson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight 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. Results: All patients showed biallelic mutations in the nonclustered protocadherin-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 of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 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 with PCDH12-related conditions. Ann Neurol 2018;84:646–655.

Original languageEnglish
Pages (from-to)638-647
Number of pages10
JournalAnnals of Neurology
Issue number5
StatePublished - Nov 2018


FundersFunder number
Broad Institute of MIT
Harvard Center for Mendelian Genomics
Mehmet Kutman Foundation
Yale University
Yale UniversityU54HG006504, RC2NS070477
Yale University
National Institutes of HealthR01NS048453, K99NS089943, R01NS098004, P30NS047101
NIH Office of the DirectorS10OD018521
Simons Foundation275275, 175303
Qatar National Research FundNPRP 6-1463-3-351, UM1 HG008900
Broad Institute


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