Genetic Variants in Craniofacial Dystonias

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Project Summary/Abstract Among the many causes of craniofacial disease are focal dystonias such as blepharospasm (BSP) and oromandibular dystonia (OMD), affecting the eyes and jaw, respectively, as well as Meige Syndrome, which combines features of both. Dystonia is the contraction of agonist and antagonist muscles, that result in abnormal postures and movement of the affected body parts. Craniofacial dystonias are poorly understood and have limited treatment options. The proposed research is relevant to public health because understanding the causes of dystonia, that interferes with vision and communication, will help to point the way toward the development of new treatment. We hypothesize that craniofacial dystonia (CFD) may be caused by both rare and common genetic variants. To identify monogenic variants, we will perform whole exome sequencing of multiplex families with CFD. To assess the contribution of common variants to CFD, we will use genome-wide association data to compute polygenic risk scores and then correlate these with disease-related imaging signatures derived from CFD patients to identify gene networks that may be driving the altered brain connectivity. To probe the functional effects of identified mutations, we will knock them into iPSC lines using genome editing tools and analyze their localizations and protein:protein interactions in neural cells as initial readouts of their pathogenic potential. These analyses will establish a cellular platform which we will also use for characterizing new craniofacial disease variants identified by our combined genetics and imaging analyses.