Multiple De-Novo Variants Resulting in Combined Axial Hypotonia with Dyskinesia and Facial Myokymia. A. Torkamani1, J. Friedman2, C. S. Bloss1, S. Topol1, E. J. Topol1, Q. Chen4, N. J. Schork1, W. H. Raskind3, A. Torkamani1 1) Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, San Diego, CA; 2) Department of Neurosciences, University of California at San Diego, San Diego, CA; 3) School of Medicine, University of Washington, Seattle, WA; 4) Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA.

   Purpose: Recent genome sequencing studies have demonstrated the potential for rapid and relatively inexpensive molecular diagnosis and treatment prioritization in genetically heterogeneous, previously characterized diseases and diagnostic odyssey cases. Of the ~100 patients successfully diagnosed by the NIH Intramural Undiagnosed Disease Program - ~83% correspond to known disease-gene relationships, ~15% correspond to novel gene associations with described diseases, and only 2% correspond to previously unknown diseases. Herein, we present the successful molecular diagnosis of a previously unknown and complex movement disorder through combined whole exome (WES) and whole genome (WGS) sequencing and confirm the functional role of ADCY5 mutations in dyskinesia with facial myokymia. Furthermore, treatment informed by the molecular diagnosis led to partial resolution of the disorder. Methods: Combined whole genome sequencing (WGS) and whole exome sequencing (WES) was performed on an affected 15-year-old female and her unaffected parents in order to identify the genetic cause of a previously undiagnosed condition involving a lifelong history of hypotonia, motor delays, abnormal involuntary movements, and sleep disturbances. A combination of inheritance-based, population-based, functional-impact-based and variant annotation-based filters applied to the WES data, then validated by WGS, resulted in three genes bearing potential candidate variants consistent with the disease. Subsequent literature-based investigation led to the conclusion that de novo nonsynonymous mutations in ADCY5 and DOCK3, as well as a rare maternally inherited nonsynonymous mutation in DOCK3 were the likely cause of the complex phenotype. Results: Mice deficient in Adcy5 develop a Parkinsonian-like phenotype and mice deficient in Dock3 develop central axonal dystrophy and sensorimotor dysfunction. Functional validation confirmed ADCY5 gain of function and immunohistochemistry of peripheral nerves confirmed neurofilament aggregates characteristic similar to those observed in Dock3 deficient mice. Motivated by the previously observed efficacy of acetazolamide in the treatment of autosomal dominant familial dyskinesia and facial myokymia due to ADCY5 mutation, initiation of acetazolamide treatment in this individual resulted in improvement of the movement disorder.

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