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The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype
Author(s) -
Yigit Gökhan,
Saida Ken,
DeMarzo Danielle,
Miyake Noriko,
Fujita Atsushi,
Yang Tan Tiong,
White Susan M.,
Wadley Alexandrea,
Toliat Mohammad R.,
Motameny Susanne,
Franitza Marek,
Stutterd Chloe A.,
Chong Pin F.,
Kira Ryutaro,
Sengoku Toru,
Ogata Kazuhiro,
Guillen Sacoto Maria J.,
Fresen Christine,
Beck Bodo B.,
Nürnberg Peter,
Dieterich Christoph,
Wollnik Bernd,
Matsumoto Naomichi,
Altmüller Janine
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23964
Subject(s) - rhoa , biology , phenotype , missense mutation , genetics , exome sequencing , in silico , small gtpase , microbiology and biotechnology , signal transduction , gene
RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher‐facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole‐exome and ultra‐deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN‐type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.