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De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features
  1. Alka Malhotra1,
  2. Alban Ziegler2,
  3. Li Shu3,
  4. Renee Perrier4,
  5. Louise Amlie-Wolf5,
  6. Elizabeth Wohler6,
  7. Nara Lygia de Macena Sobreira6,
  8. Estelle Colin2,
  9. Adeline Vanderver7,8,
  10. Omar Sherbini7,
  11. Katrien Stouffs9,
  12. Emmanuel Scalais10,
  13. Alessandro Serretti11,
  14. Magalie Barth2,
  15. Benjamin Navet2,
  16. Paul Rollier2,
  17. Hui Xi3,
  18. Hua Wang3,
  19. Hainan Zhang12,
  20. Denise L Perry1,
  21. Alessandra Ferrarini13,
  22. Roberto Colombo14,
  23. Alexander Pepler15,16,
  24. Adele Schneider17,
  25. Kiyotaka Tomiwa18,
  26. Nobuhiko Okamoto19,
  27. Naomichi Matsumoto20,
  28. Noriko Miyake20,
  29. Ryan Taft1,
  30. Xiao Mao3,
  31. Dominique Bonneau2
  1. 1Illumina Inc, San Diego, California, USA
  2. 2Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, Angers, France
  3. 3Maternal and Child Health Hospital of Hunan Province, Changsha, China
  4. 4Department of Medical Genetics and Pediatrics, University of Calgary, Calgary, Alberta, Canada
  5. 5Nemours A.I. Dupont Hospital for Children, Wilmington, Delaware, USA
  6. 6McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  7. 7Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  8. 8Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  9. 9Centre for Medical Genetics, UZ Brussel, Brussels, Belgium
  10. 10Division of Paediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
  11. 11Department of Biomedical and NeuroMotor Sciences, Bologna University, Bologna, Italy
  12. 12Department of Neurology, The Second Xiangya Hospital, Central South University, Hunan, China
  13. 13Italian Hospital of Lugano and University of Lugano, Lugano, Switzerland
  14. 14Center for the Study of Rare Hereditary Diseases, Catholic University and Policlinico Agostino Gemelli University Hospital, Milan, Italy
  15. 15Praxis für Humangenetik, Tuebingen, Germany
  16. 16CeGaT GmbH, Tubingen, Baden-Württemberg, Germany
  17. 17Wills Eye Hospital, Philadelphia, Pennsylvania, USA
  18. 18Todaiji Ryoiku Hospital for Children, Kyoto, Japan
  19. 19Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan
  20. 20Department of Human Genetics, Yokohama City University, Yokohama, Kanagawa, Japan
  1. Correspondence to Dr Alka Malhotra, Illumina Inc., San Diego, CA 92122, USA; amalhotra{at}


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.

  • genetics, medical
  • gain of function mutation
  • mutation, missense

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  • AM, AZ and LS are joint first authors.

  • RT, XM and DB are joint senior authors.

  • AM, AZ and LS contributed equally.

  • RT, XM and DB contributed equally.

  • Contributors All the authors approved the final content of the manuscript. AM, AZ, and LS monitored the cohort gathering, interpreted the data (clinical and molecular), conceived and designed the work and wrote the manuscript. DB, XM and RT supervised the interpretation of data and the writing of the manuscript. RP, AV, NaM and NoM contributed clinical information, assessment of intellectual content and MRI interpretation. LA-W, AF and RC contributed clinical information and assessment of intellectual content. EW and NLdMS contributed molecular information, analysis and interpretation of the data and assessment of intellectual content. OS contributed clinical information and MRI interpretation. AP contributed clinical and molecular information and assessment of intellectual content. DLP provided analysis and interpretation of the data, writing and reviewing of the paper, and assessment of intellectual content. MB, AlS, AdS, KT, NO, HX and HW contributed clinical information and interpretation of the data. BN and KS provided molecular information, and analysis and interpretation of the data. PR contributed to the figure design and cohort gathering. EC, HZ and ES contributed to the data analysis and MRI interpretation.

  • Funding This study was funded by Baylor-Hopkins Center for Mendelian Genomics (NHGRI UM1 HG006542).

  • Competing interests AM, DLP and RT are full-time employees of Illumina, Inc. AP is an employee of CeGaT GmbH, Germany.

  • Patient consent for publication Parental/guardian consent obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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