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TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility

European Journal of Human Genetics volume 29, pages 1669–1676 (2021)Cite this article

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Abstract

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68–14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name “TAB2-related syndrome”.

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Fig. 1: Overview of all deletions leading to our candidate gene TAB2.
Fig. 2: Clinical photographs of patients with a TAB2 deletion.
Fig. 3: Clinical photographs of patients with a TAB2 variant.

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Acknowledgements

We would like to express our gratitude to all the children and families for their participation. We also thank Kate McIntyre for editing the manuscript and the members of the Groningen Genomic Coordination Centre. Our special thanks go to Pauline Bouman, our contact for the Chromosome 6 Facebook group.

Author contributions

Conceptualization: AE, CMAR, WSK; Data curation: AE; Funding acquisition: AE, BF, CMAR, WSK; Investigation: AE, CMAR, WSK; Methodology: AE, CMAR, WSK; Resources: AE, EKSML, BF, PAT, KL, BBAV, TD, YJV, TR, MPB, MTRR, WSK; Supervision: WSK; Visualization: AE, PD; Writing – original draft: AE; Writing – review & editing: AE, EKSML, BF, PAT, KL, BBAV, TD, YJV, TR, MPB, MTRR, CMAR, WSK.

Funding

This work was supported by a grant from ZonMw (113312101) and by crowd-funding organised by Chromosome 6 parents. AE is recipient of a Junior Scientific Masterclass MD/PhD scholarship of the University Medical Center Groningen.

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Authors and Affiliations

  1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Aafke Engwerda, Katharina Löhner, Trijnie Dijkhuizen, Yvonne J. Vos, Patrick Deelen, Conny M. A. van Ravenswaaij-Arts & Wilhelmina S. Kerstjens-Frederikse

  2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    Erika K. S. M. Leenders, Bert B. A. de Vries & Tuula Rinne

  3. Vanboeijen, Assen, The Netherlands

    Barbara Frentz

  4. Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands

    Paulien A. Terhal & Patrick Deelen

  5. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Maarten P. van den Berg

  6. Department of Paediatric Cardiology, University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Groningen, The Netherlands

    Marc T. R. Roofthooft

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  1. Aafke Engwerda
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Correspondence to Wilhelmina S. Kerstjens-Frederikse.

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The accredited Medical Ethics Review Committee of the University Medical Center Groningen waived full ethical evaluation because, according to Dutch guidelines, no ethical approval is necessary if medical information that was already available is used anonymously and no extra tests have to be performed.

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Engwerda, A., Leenders, E.K.S.M., Frentz, B. et al. TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility. Eur J Hum Genet 29, 1669–1676 (2021). https://doi.org/10.1038/s41431-021-00948-0

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