Abstract
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 language | English (US) |
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Pages (from-to) | 638-647 |
Number of pages | 10 |
Journal | Annals of neurology |
Volume | 84 |
Issue number | 5 |
DOIs | |
State | Published - Nov 2018 |
Funding
This work was supported by the NIH R01NS048453 and R01NS098004 to J.G.G., P30NS047101 for imaging support, K99NS089943 to A.G.-G., the Yale Center for Mendelian Disorders U54HG006504, RC2NS070477, and the Gregory M. Kiez and Mehmet Kutman Foundation to M.G., Simons Foundation Grants 175303 and 275275, QNRF grant NPRP 6-1463-3-351 to J.G.G. and T.B.-O., and UM1 HG008900 to the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG). We acknowledge the Yale Biomedical High-Performance Computing Center for data analysis and storage; the Yale Program on Neurogenetics and the Yale Center for Human Genetics and Genomics; the Center for Inherited Disease Research for genotyping; and the Simons Foundation Autism Research Initiative. Sequencing was provided, in part, by a gift from BGI and Illumina, Inc., to Rady Children's Hospital, San Diego for undiagnosed patients. Consortium for Autosomal Recessive Intellectual Disability (CARID) supported patient ascertainment. This work was supported by the NIH R01NS048453 and R01NS098004 to J.G.G., P30NS047101 for imaging support, K99NS089943 to A.G.-G., the Yale Center for Mendelian Disorders U54HG006504, RC2NS070477, and the Gregory M. Kiez and Mehmet Kutman Foundation to M.G., Simons Foundation Grants 175303 and 275275, QNRF grant NPRP 6-1463-3-351 to J.G.G. and T.B.-O., and UM1 HG008900 to the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG).
ASJC Scopus subject areas
- Neurology
- Clinical Neurology