Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus

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  • 1 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut;
  • | 2 Department of Genetics, Washington University School of Medicine, St. Louis, Missouri;
  • | 3 Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut;
  • | 4 School of Pharmacy, University College London, London, United Kingdom;
  • | 5 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;
  • | 6 Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut;
  • | 7 Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts;
  • | 8 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;
  • | 9 Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts; and
  • | 10 Broad Institute of MIT and Harvard, Cambridge, Massachusetts
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Congenital hydrocephalus (CH), characterized by incomplete clearance of CSF and subsequent enlargement of brain ventricles, is the most common congenital brain disorder. The lack of curative strategies for CH reflects a poor understanding of the underlying pathogenesis. Herein, the authors present an overview of recent findings in the pathogenesis of CH from human genetic studies and discuss the implications of these findings for treatment of CH. Findings from these omics data have the potential to reclassify CH according to a molecular nomenclature that may increase precision for genetic counseling, outcome prognostication, and treatment stratification. Beyond the immediate patient benefits, genomic data may also inform future clinical trials and catalyze the development of nonsurgical, molecularly targeted therapies. Therefore, the authors advocate for further application of genomic sequencing in clinical practice by the neurosurgical community as a diagnostic adjunct in the evaluation and management of patients diagnosed with CH.

ABBREVIATIONS

CH = congenital hydrocephalus; CNV = copy number variant; DNM = de novo mutation; HSAS = X-linked hydrocephalus; NDD = neurodevelopmental disorder; PH = periventricular hypertropia; SNV = single-nucleotide variant; WES = whole-exome sequencing; WGS = whole-genome sequencing; XHMM = eXome-Hidden Markov Model.

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