TY - JOUR
T1 - De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features
AU - Malhotra, Alka
AU - Ziegler, Alban
AU - Shu, Li
AU - Perrier, Renee
AU - Amlie-Wolf, Louise
AU - Wohler, Elizabeth
AU - Lygia de Macena Sobreira, Nara
AU - Colin, Estelle
AU - Vanderver, Adeline
AU - Sherbini, Omar
AU - Stouffs, Katrien
AU - Scalais, Emmanuel
AU - Serretti, Alessandro
AU - Barth, Magalie
AU - Navet, Benjamin
AU - Rollier, Paul
AU - Xi, Hui
AU - Wang, Hua
AU - Zhang, Hainan
AU - Perry, Denise L
AU - Ferrarini, Alessandra
AU - Colombo, Roberto
AU - Pepler, Alexander
AU - Schneider, Adele
AU - Tomiwa, Kiyotaka
AU - Okamoto, Nobuhiko
AU - Matsumoto, Naomichi
AU - Miyake, Noriko
AU - Taft, Ryan
AU - Mao, Xiao
AU - Bonneau, Dominique
N1 - © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/8/20
Y1 - 2020/8/20
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>A (p.Arg483His) in three cases and c.367T>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.
AB - 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>A (p.Arg483His) in three cases and c.367T>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.
UR - http://www.scopus.com/inward/record.url?scp=85094950767&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2020-107137
DO - 10.1136/jmedgenet-2020-107137
M3 - Article
C2 - 32820033
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
M1 - 107137
ER -