Alka Malhotra # 1 , Alban Ziegler # 2 , Li Shu # 3 , Renee Perrier 4 , Louise Amlie-Wolf 5 , Elizabeth Wohler 6 , Nara Lygia de Macena Sobreira 6 , Estelle Colin 2 , Adeline Vanderver 7 8 , Omar Sherbini 7 , Katrien Stouffs 9 , Emmanuel Scalais 10 , Alessandro Serretti 11 , Magalie Barth 2 , Benjamin Navet 2 , Paul Rollier 2 , Hui Xi 3 , Hua Wang 3 , Hainan Zhang 12 , Denise L Perry 13 , Alessandra Ferrarini 14 , Roberto Colombo 15 , Alexander Pepler 16 17 , Adele Schneider 18 , Kiyotaka Tomiwa 19 , Nobuhiko Okamoto 20 , Naomichi Matsumoto 21 , Noriko Miyake 21 , Ryan Taft # 13 , Xiao Mao # 3 , Dominique Bonneau # 2
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.
Keywords: gain of function mutation; genetics, medical; mutation, missense.
© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict of interest statement
Competing interests: AM, DLP and RT are full-time employees of Illumina, Inc. AP is an employee of CeGaT GmbH, Germany.
- Illumina Inc, San Diego, California, USA email@example.com.
- Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, Angers, France.
- Maternal and Child Health Hospital of Hunan Province, Changsha, China.
- Department of Medical Genetics and Pediatrics, University of Calgary, Calgary, Alberta, Canada.
- Nemours A.I. Dupont Hospital for Children, Wilmington, Delaware, USA..
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
- Centre for Medical Genetics, UZ Brussel, Brussels, Belgium.
- Division of Paediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
- Department of Biomedical and NeuroMotor Sciences, Bologna University, Bologna, Italy.
- Department of Neurology, The Second Xiangya Hospital, Central South University, Hunan, China.
- Illumina Inc, San Diego, California, USA.
- Italian Hospital of Lugano and University of Lugano, Lugano, Switzerland.
- Center for the Study of Rare Hereditary Diseases, Catholic University and Policlinico Agostino Gemelli University Hospital, Milan, Italy.
- Praxis für Humangenetik, Tuebingen, Germany.
- CeGaT GmbH, Tubingen, Baden-Württemberg, Germany.
- Wills Eye Hospital, Philadelphia, Pennsylvania, USA.
- Todaiji Ryoiku Hospital for Children, Kyoto, Japan.
- Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan.
- Department of Human Genetics, Yokohama City University, Yokohama, Kanagawa, Japan.
# Contributed equally.