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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