RT Journal Article SR Electronic T1 Recessive inactivating mutations in TBCK, encoding a Rab GTPase-activating protein that modulates mTOR signaling, cause severe infantile syndromic encephalopathy JF bioRxiv FD Cold Spring Harbor Laboratory SP 036111 DO 10.1101/036111 A1 Jessica X. Chong A1 Viviana Caputo A1 Ian G. Phelps A1 Lorenzo Stella A1 Lisa Worgan A1 Jennifer C. Dempsey A1 Alina Nguyen A1 Vincenzo Leuzzi A1 Richard Webster A1 Antonio Pizzuti A1 Colby T. Marvin A1 Gisele E. Ishak A1 Simone Ardern–Holmes A1 Zara Richmond A1 Univ of Washington Center for Mendelian Genomics A1 Michael J. Bamshad A1 Xilma R. Ortiz-Gonzalez A1 Marco Tartaglia A1 Maya Chopra A1 Dan Doherty YR 2016 UL http://biorxiv.org/content/early/2016/01/06/036111.abstract AB Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a previously unrecognized syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, corpus callosum dysgenesis, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1 domain-containing kinase) were independently identified by Whole-Exome Sequencing (WES) as the cause of this condition in four unrelated families. Matching these families was facilitated by sharing phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin cytoskeleton dynamics, and mTOR signaling. Two of the three mutations are predicted to truncate the protein (c.376C>T [p.Arg126*] and c.1363A>T [p.Lys455*]), and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A [p.Arg511His], alters a conserved residue within the TBC1 domain. Structural analysis implicates Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicts impaired GAP function in the corresponding mutant. These results suggest loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.