TY - JOUR T1 - De novo missense variants in <em>LMBRD2</em> are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107137 SP - jmedgenet-2020-107137 AU - Alka Malhotra AU - Alban Ziegler AU - Li Shu AU - Renee Perrier AU - Louise Amlie-Wolf AU - Elizabeth Wohler AU - Nara Lygia de Macena Sobreira AU - Estelle Colin AU - Adeline Vanderver AU - Omar Sherbini AU - Katrien Stouffs AU - Emmanuel Scalais AU - Alessandro Serretti AU - Magalie Barth AU - Benjamin Navet AU - Paul Rollier AU - Hui Xi AU - Hua Wang AU - Hainan Zhang AU - Denise L Perry AU - Alessandra Ferrarini AU - Roberto Colombo AU - Alexander Pepler AU - Adele Schneider AU - Kiyotaka Tomiwa AU - Nobuhiko Okamoto AU - Naomichi Matsumoto AU - Noriko Miyake AU - Ryan Taft AU - Xiao Mao AU - Dominique Bonneau Y1 - 2020/08/20 UR - http://jmg.bmj.com/content/early/2020/08/19/jmedgenet-2020-107137.abstract N2 - Objective To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.Methods Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.Results LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G&gt;A (p.Arg483His) in three cases and c.367T&gt;C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.Conclusion These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene. ER -