|Title||Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Guemez-Gamboa, A, Çağlayan, AOkay, Stanley, V, Gregor, A, Zaki, MS, Saleem, SN, Musaev, D, McEvoy-Venneri, J, Belandres, D, Akizu, N, Silhavy, JL, Schroth, J, Rosti, ROzgur, Copeland, B, Lewis, SM, Fang, R, Issa, MY, Per, H, Gümüş, H, Bayram, AKacar, Kumandaş, S, Akgümüş, GTuğce, Erson-Omay, EZ, Yasuno, K, Bilguvar, K, Heimer, G, Pillar, N, Shomron, N, Weissglas-Volkov, D, Porat, Y, Einhorn, Y, Gabriel, S, Ben-Zeev, B, Günel, M, Gleeson, JG|
|Date Published||2018 Nov|
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.
|Alternate Journal||Ann. Neurol.|
|PubMed Central ID||PMC6510237|
|Grant List|| / / Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) / |
P30NS047101 / GF / NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
175303 / / Simons Foundation /
275275 / / Simons Foundation /
R00 NS089943 / NS / NINDS NIH HHS / United States
R01NS098004 / GF / NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54HG006504 / / Yale Center for Mendelian Disorders /
RC2NS070477 / / Yale Center for Mendelian Disorders /
R01 NS098004 / NS / NINDS NIH HHS / United States
K99 NS089943 / NS / NINDS NIH HHS / United States
R01NS048453 / GF / NIH HHS / United States