3757 Human Molecular Genetics, 2020, Vol. 29, No. 23 3757–3764 doi: 10.1093/hmg/ddaa245 Advance Access Publication Date: 18 November 2020 General Article GENERAL ARTICLE TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly Valerie Jacquemin 1,† , Mathieu Antoine 1 , Sarah Duerinckx 1,2 , Annick Massart 1,3 , Julie Desir 4 , Camille Perazzolo 1 , Marie Cassart 5 , Dominique Thomas 5 , Valérie Segers 6 , Sophie Lecomte 6 , Marc Abramowicz 1,7,†, * and Isabelle Pirson 1,† 1 IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium, 2 Neurology Department, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium, 3 Department of Nephrology, Hôpital Universitaire d’Anvers, 2650 Edegem, Belgium, 4 Human Genetics Center, Institute of Pathology and Genetics, 6041 Charleroi, Belgium, 5 Department of Gynecology and Obstetrics, Hôpitaux Iris Sud, 1050 Brussels, Belgium, 6 Department of Anatomopathology, CHU Brugmann, 1020 Brussels, Belgium and 7 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland *To whom correspondence should be addressed. Tel: +44 76 226 18 22; Email: marc.abramowicz@unige.ch Abstract Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype. Introduction Hydrocephalus is a potentially devastating condition whose long-term complications include cerebral palsy, intellectual disability, epilepsy, blindness and early death (1). Hydrocephalus is defined as a disturbance of cerebrospinal fluid (CFS) home- ostasis which results in progressive ventricular dilatation due to increased CSF pressure (2). Because CSF pressure cannot readily be measured in utero, ventriculomegaly, i.e. the enlargement of the cerebral ventricles, is often used as a marker of fetal or congenital hydrocephalus (CH). Ventriculomegaly is the most † These authors share senior authorship. Received: September 11, 2020. Revised: November 9, 2020. Accepted: November 10, 2020 © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com common central nervous system anomaly detected by prenatal ultrasound and is a sensitive indicator of CH (3). Based on its underlying origin, hydrocephalus is categorized as secondary i.e. acquired when resulting from an identified extrinsic event or primary i.e. developmental when no causal event is identified. Primary congenital hydrocephalus (PCH) is further categorized as syndromic or isolated/non-syndromic depending on the presence or absence of additional congenital anomalies. PCH has an incidence of about 0.2–0.8/1000 live births (4), and a genetic etiology can be suspected in about 40% of cases (5). Downloaded from https://academic.oup.com/hmg/article/29/23/3757/5987083 by guest on 18 December 2021