RT Journal Article
SR Electronic
T1 Complex genetic network underlying the convergent of Rett Syndrome like (RTT-L) phenotype in neurodevelopmental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.11.899658
DO 10.1101/2020.01.11.899658
A1 Eric Frankel
A1 Julius Dodson
A1 Megan Sharifi
A1 Roshan Pillai
A1 Keri Ramsey
A1 Raj Gupta
A1 Molly Brzezinski
A1 Pooja Venugopal
A1 Lorida Llaci
A1 Brittany Gerald
A1 Gabrielle Mills
A1 Newell Belnap
A1 Meredith Sanchez-Castillo
A1 Chris D. Balak
A1 Ana M. Claasen
A1 Szabolcs Szelinger
A1 Wayne M. Jepsen
A1 Ashley L. Siniard
A1 Ryan Richholt
A1 Matt De Both
A1 Marcus Naymik
A1 Isabelle Schrauwen
A1 Ignazio S. Piras
A1 David W. Craig
A1 Matthew J. Huentelman
A1 Vinodh Narayanan
A1 Sampathkumar Rangasamy
YR 2020
UL http://biorxiv.org/content/early/2020/01/14/2020.01.11.899658.abstract
AB Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. Patients with features of classical Rett syndrome, but do not fulfill all the diagnostic criteria (e.g. absence of a MECP2 mutation), are defined as atypical Rett syndrome. Genes encoding for cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are more commonly found in patients with atypical Rett syndrome. Nevertheless, a subset of patients who are recognized to have an overlapping phenotype with RTT but are lacking a mutation in a gene that causes typical or atypical RTT are described as having Rett syndrome like phenotype (RTT-L). Whole Exome Sequencing (WES) of 8 RTT-L patients from our cohort revealed mutations in the genes GABRG2, GRIN1, ATP1A2, KCNQ2, KCNB1, TCF4, SEMA6B, and GRIN2A, which are seemingly unrelated to Rett syndrome genes. We hypothesized that the phenotypic overlap in RTT and RTT-L is caused by mutations in genes that affect common cellular pathways critical for normal brain development and function. We annotated the list of genes identified causing RTT-L from peer-reviewed articles and performed a protein-protein interaction (PPI) network analysis. We also investigated their interaction with RTT (typical or atypical) genes such as MECP2, CDKL5, NTNG1, and FOXG1. We found that the RTT-L-causing genes were enriched in the biological pathways such as circadian entrainment, the CREB pathway, and RET signaling, and neuronal processes like ion transport, synaptic transmission, and transcription. We conclude that genes that significantly interact with the PPI network established by RTT genes cause RTT-L, explaining the considerable feature overlap between genes that are indicated for RTT-L and RTT.