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.
All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteris- tic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with fre- quent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endo- thelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth.
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