REPORT Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder Susan M. Hiatt, 1 Michelle L. Thompson, 1 Jeremy W. Prokop, 2 James M.J. Lawlor, 1 David E. Gray, 1 E. Martina Bebin, 3 Tuula Rinne, 4 Marlies Kempers, 4 Rolph Pfundt, 4 Bregje W. van Bon, 4 Cyril Mignot, 5,6,7 Caroline Nava, 5,8 Christel Depienne, 8,9 Louisa Kalsner, 10 Anita Rauch, 11,12 Pascal Joset, 11 Ruxandra Bachmann-Gagescu, 11 Ingrid M. Wentzensen, 13 Kirsty McWalter, 13 and Gregory M. Cooper 1, * Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social- media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/ threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the re- maining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p ¼ 2.46 3 10 À6 ). We also find that exome sequencing provides lower coverage and ap- pears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2’s visibility in many clin- ical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease. Developmental delay and intellectual disability (DD and ID), attention-deficient/hyperactivity disorder (ADHD), schizophrenia, language communication disorders, autism spectrum disorders (ASDs), and motor and tic disorders lie under a more general umbrella of neurodevelopmental dis- orders (NDDs). 1,2 Although these are traditionally catego- rized into discrete disease entities, many symptoms are not unique to a single NDD. Furthermore, many genes have been associated with multiple NDDs, 3 and new ge- netic associations continue to be discovered. This is partic- ularly true given the recent acceleration in large-scale sequencing and cross-site genotype-phenotype ‘‘match- making’’ efforts. 4,5 Through a Clinical Sequencing Exploratory Research (CSER) project focused on sequence-driven diagnoses for probands with unexplained DD and/or ID, 6 we identified variation likely to be deleterious in BRSK2 (MIM: 609236) in four unrelated probands. BRSK2 encodes a serine/threo- nine-protein kinase, which is involved in axonogenesis and the polarization of cortical neurons. 7 BRSK2 is pre- dicted to be relatively intolerant to protein-altering varia- tion in the general population (%ExAC v2 residual variation intolerance score [RVIS] ¼ 4.9462%, 8 pLI score (probability that a gene is intolerant to a loss of function mutation) ¼ 0.78 9 ). In each proband, the BRSK2 variant was prioritized, after filtering and manual curation, as the most compelling disease-candidate variant of interest (see details by Bowling and colleagues for additional informa- tion about the cohort and analytical methods 6 ). Although these observations suggest BRKS2 as a strong candidate NDD-associated gene, we sought additional cases via GeneMatcher 5 to support pathogenicity. GeneMatcher is a database developed as part of the MatchMaker Exchange and has been shown to facilitate rare-disease-gene discovery. 10 Information about five additional affected probands who were found by research or diagnostic sequencing (Table 1) and who had variants likely to be deleterious in BRSK2 was independently submitted to GeneMatcher. Informed consent to publish de-identified data was obtained from all affected individuals and/or fam- ilies (see Supplemental Material and Methods). Altogether, the affected probands ranged in age from 3 years and 1 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; 2 Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA; 3 Department of Neurology, University of Alabama Birmingham, Birmingham, AL 35294, USA; 4 Department of Human Ge- netics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; 5 De ´partement de Ge ´ne ´tique, Groupe Hospitalier Pitie ´-Salpe ˆtrie `re, Assis- tance Publique – Ho ˆpitaux de Paris, Paris 75013, France; 6 Centres de Re ´fe ´rence Maladies Rares, De ´ficiences Intellectuelles de Causes Rares, Paris 75013, France; 7 Groupes de Recherche Clinique Paris Sorbonne De ´ ficience Intellectuelle et Autisme, Paris 75013, France; 8 Faculte ´ de Me ´decine, Institut du Cerveau et de la Moelle e ´pinie `re, Sorbonne Universite ´, Paris 75013, France; 9 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany; 10 Connecticut Children’s Medical Center, Farmington, CT 06032, USA; 11 Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland; 12 Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program, University of Zurich, Zurich 8032, Switzerland; 13 GeneDx, Gaithersburg, MD 20877, USA *Correspondence: gcooper@hudsonalpha.org https://doi.org/10.1016/j.ajhg.2019.02.002. The American Journal of Human Genetics 104, 701–708, April 4, 2019 701 Ó 2019 American Society of Human Genetics.