Genomic Sequencing Approaches Identifies Novel Rare Variants in Patients with Mendelian Neurologic Diseases. E. KARACA1, D. PEHLIVAN1, T. HAREL1, S. Weitzer2, H. Shiraishi2, T. GAMBIN1, Y. BAYRAM1, W. Wiszniewski1, S. N. JHANGIANI3, G. YESIL4, S. ISIKAY5, O. OZALP YUREGIR6, S. BOZDOGAN6, H. ASLAN6, T. TOS7, D. GUL8, B. YILMAZ9, O. COGULU9, K. KARAER10, H. ULUCAN11, D. Muzny3, M. SEVEN11, A. YUKSEL11, T. CLAUSEN12, T. Tuschl13, A. HESS14, R. A. GIBBS1,3, J. MARTINEZ2, J. M. PENNINGER2, J. R. LUPSKI1,15,16 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria; 3) Human Genome Sequencing Center, Baylor College of Medicine, Houston TX, USA; 4) Department of Medical Genetics, Bezmialem University, Istanbul, Turkey; 5) Gaziantep Children`s Hospital, Gaziantep, Turkey; 6) Department of Medical Genetics, Numune Training and Research Hospital, Adana, Turkey; 7) Department of Medical Genetics, Sami Ulus Childrens Hospital, Ankara, Turkey; 8) Department of Medical Genetics, Gülhane Military Medical School, Ankara, Turkey; 9) Department of Medical Genetics, Ege University, Faculty of Medicine, 35100, Izmir Turkey; 10) Intergen Genetic Center, Ankara, Turkey; 11) Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul, Turkey; 12) IMP, Institute of Molecular Pathology, 1030 Vienna; 13) Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA; 14) Institute for Experimental Pharmacology Friedrich-Alexander University Erlangen-Nuremberg, Germany, and Campus Support Facility (CSF), Vienna BioCentre, Vienna; 15) Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; 16) Texas Childrens Hospital, Houston, TX, USA.

   Development of the human nervous system involves a variety of complex interactions between fundamental cellular processes including proliferation, differentiation, migration and apoptosis. The advent of next generation sequencing has enabled rapid identification of numerous genes and mechanisms that contribute to human neurogenesis. However, considering the magnitude and complexity of the mechanisms involved, the search for genes underlying Mendelian neurological disease is far from complete. We applied whole exome sequencing (WES) to a cohort of 114 Turkish patients with congenital brain malformations from 82 mostly consanguineous families. In 40 patients (35%), WES revealed deleterious mutations in known genes. An additional 14 patients (12%) harbored deleterious mutations in known genes but were noted to have distinctive clinical features when compared to the available literature, thus representing phenotypic expansion. Potential disease causing variants were identified in novel candidate genes in the remaining 60 patients (52%) and segregated with the phenotype in available family members. Among the genes identified, we found a homozygous CLP1 rare single variant (c.G419A; pR240H) in 7 unrelated families. CLP1 is a RNA kinase involved in tRNA splicing. We recently showed that this homozygous missense mutation leads to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reducing pre-tRNA cleavage activity and resulting in accumulation of linear tRNA introns. Furthermore, we showed that mice carrying kinase-dead CLP1 displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. The use of genomic sequencing approaches, along with other genome-wide interrogation technologies, is invaluable in the identification of causative rare variants in families segregating Mendelian disease traits. We expect that these will provide novel insights into human nervous system development and human biology, as well as human neurologic disease.

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