PURPOSE: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C2H2 domain-containing transcription factor. METHODS: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals. RESULTS: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia. CONCLUSION: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.

Center for Human Disease Modeling Duke University Medical Center Durham NC USA

Department of Biological Sciences National University of Medical Sciences Rawalpindi Pakistan

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General Faculty Hospital Prague Czech Republic

Department of Neurology P J Safarik University Kosice Slovak Republic

Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Epilepsy Research Centre Department of Medicine University of Melbourne Austin Health Heidelberg VIC Australia

Human Molecular Genetics Laboratory Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering Faisalabad Pakistan

Institut für Humangenetik Helmholtz Zentrum München Munich Germany

Institut für Humangenetik Technische Universität München Munich Germany

Institute of Medical Genetics Medical School of Vienna Vienna Austria

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Lehrstuhl für Neurogenetik Technische Universität München Munich Germany

Munich Cluster for Systems Neurology SyNergy Munich Germany

Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics Royal Children's Hospital Parkville Australia

Pakistan Institute of Engineering and Applied Sciences Islamabad Pakistan

Population Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research and University of Melbourne Department of Medical Biology and School of Mathematics and Statistics Parkville VIC Australia

University of Melbourne Department of Paediatrics Royal Children's Hospital and Florey and Murdoch Children's Research Institute Parkville VIC Australia

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