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A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene

European Journal of Human Genetics volume 30, pages 1083–1087 (2022)Cite this article

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Abstract

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5’ transduction and hallmarks of target-primed reverse transcription. The 20-bp 5’ transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

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Fig. 1: Identification and validation of a de novo SVA insertion in SRCAP exon 13.
Fig. 2: Characterization and pathogenicity of the exonic SVA insertion.

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Data availability

Sequencing data supporting the findings of this study are available upon reasonable request.

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Acknowledgements

We thank the patient and family for their participation and support. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal.

Funding

EAL was supported by the NIH (DP2 AG0724), Suh Kyungbae Foundation, Charles H. Hood foundation, and the Allen Discovery Center program of the Paul G. Allen Family Foundation. BZ was supported by the Manton Center Pilot Project Award and Rare Disease Research Fellowship. MHW is supported by an Early Career Award from the Thrasher Research Fund. PBA’s research work is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, R01AR068429-01, National Human Genome Research Institute, 1R01HG011798-01A1 and “Because of Bella” foundation. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141, as well as the National Institutes of Health grants MH115957 and HD081256. Sanger sequencing was performed by the Boston Children’s Hospital IDDRC Molecular Genetics Core Facility supported by NIH award U54HD090255 from the National Institute of Child Health and Human Development.

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Authors and Affiliations

  1. Division of Genetics and Genomics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Boxun Zhao, Jill A. Madden, Jasmine Lin, Gerard T. Berry, Monica H. Wojcik, Eunjung Alice Lee & Pankaj B. Agrawal

  2. Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA

    Boxun Zhao, Jill A. Madden, Jasmine Lin, Gerard T. Berry, Monica H. Wojcik, Eunjung Alice Lee & Pankaj B. Agrawal

  3. The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Boxun Zhao, Monica H. Wojcik, Eunjung Alice Lee & Pankaj B. Agrawal

  4. Division of Newborn Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Jasmine Lin, Monica H. Wojcik & Pankaj B. Agrawal

  5. Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Xuefang Zhao, Harrison Brand & Michael Talkowski

  6. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Xuefang Zhao, Harrison Brand & Michael Talkowski

  7. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Xuefang Zhao, Harrison Brand & Michael Talkowski

Authors
  1. Boxun Zhao
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  2. Jill A. Madden
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  9. Eunjung Alice Lee
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  10. Pankaj B. Agrawal
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Contributions

BZ characterized the insertion variant, designed and analyzed experimental validation assays, performed RNA-seq analysis, qRT-PCR, and splicing analysis for pathogenicity confirmation, made all figures and supplementary materials, and wrote the manuscript. JAM coordinated samples, clinical record, and sequencing data collections, made Table 1 for clinical presentation, and wrote the manuscript. JL performed all experimental validation assays, and edited the manuscript. GTB enrolled the patient. MHW helped analyze genome sequencing results that identified the potential variant, and edited the manuscript. XZ, HB, and MT performed SV data processing, identified the potential variant, and edited the manuscript. EAL and PBA directed the overall research and revised the manuscript.

Corresponding authors

Correspondence to Eunjung Alice Lee or Pankaj B. Agrawal.

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Competing interests

PBA is on the Scientific Advisory Board of Illumina, Inc. and GeneDx, Inc. Other authors declare no competing interests.

Ethics approval and consent to participate

The proband and her family were enrolled into the Gene Discovery Core at The Manton Center for Orphan Disease Research approved by the IRB (10-02-0053) at Boston Children’s Hospital. Written informed consents were obtained from the patient and family members.

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Zhao, B., Madden, J.A., Lin, J. et al. A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene. Eur J Hum Genet 30, 1083–1087 (2022). https://doi.org/10.1038/s41431-022-01137-3

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