De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features

Authors

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}

# Contributed equally.

Illumina Inc, San Diego, California, USA amalhotra@illumina.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.

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.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features

Abstract

Conflict of interest statement

References

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