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A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort

European Journal of Human Genetics volume 31, pages 761–768 (2023)Cite this article

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Abstract

About 0.3% of all variants are due to de novo mobile element insertions (MEIs). The massive development of next-generation sequencing has made it possible to identify MEIs on a large scale. We analyzed exome sequencing (ES) data from 3232 individuals (2410 probands) with developmental and/or neurological abnormalities, with MELT, a tool designed to identify MEIs. The results were filtered by frequency, impacted region and gene function. Following phenotype comparison, two candidates were identified in two unrelated probands. The first mobile element (ME) was found in a patient referred for poikilodermia. A homozygous insertion was identified in the FERMT1 gene involved in Kindler syndrome. RNA study confirmed its pathological impact on splicing. The second ME was a de novo Alu insertion in the GRIN2B gene involved in intellectual disability, and detected in a patient with a developmental disorder. The frequency of de novo exonic MEIs in our study is concordant with previous studies on ES data. This project, which aimed to identify pathological MEIs in the coding sequence of genes, confirms that including detection of MEs in the ES pipeline can increase the diagnostic rate. This work provides additional evidence that ES could be used alone as a diagnostic exam.

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Fig. 1: MEs detection pipeline with the MELT tool on ES data.
Fig. 2: Filters applied to MELT detected MEs in 2394 probands.
Fig. 3: FERMT1, GRIN2B and NPRL3 ME candidates validation and segregation.
Fig. 4: FERMT1 exon 7 skipping in proband’s cDNA fibroblasts.

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Data availability

The data are available on request from the corresponding author.

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Acknowledgements

We thank the probands and their families for their participation; and the Centre De Calcul (CCuB) at the University of Burgundy for providing technical support and management of the informatics core facility.

Funding

This work was supported by grants from the Regional Council of Burgundy (to C.T.‐R.), the FEDER 2017, PARI 2017, and CIFRE (ANRT) between Laboratoire Cerba and Regional Council of Burgundy for the doctoral work at Laboratoire Cerba and GAD.

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Authors and Affiliations

  1. UMR1231 GAD, Inserm—Université Bourgogne-Franche Comté, Dijon, France

    Philippine Garret, Martin Chevarin, Antonio Vitobello, Simon Verdez, Emilie Tisserant, Pierre Vabres, Orlane Prevel, Christophe Philippe, Anne-Sophie Denommé-Pichon, Ange-Line Bruel, Frédéric Tran Mau-Them, Hana Safraou, Christel Thauvin-Robinet, Laurence Faivre & Yannis Duffourd

  2. Laboratoire, CERBA, Saint-Ouen l’Aumône, France

    Philippine Garret, Aïcha Boughalem, Jean-Marc Costa & Detlef Trost

  3. Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, Dijon University Hospital, Dijon, France

    Martin Chevarin, Antonio Vitobello, Simon Verdez, Emilie Tisserant, Christophe Philippe, Anne-Sophie Denommé-Pichon, Ange-Line Bruel, Frédéric Tran Mau-Them, Hana Safraou, Christel Thauvin-Robinet & Yannis Duffourd

  4. UMR 1231, Faculty of Medicine, University of Burgundy-iSITE—INSERM, Dijon, France

    Cyril Fournier

  5. Unit for innovation in genetics and epigenetic in oncology, Dijon University Hospital, Dijon, France

    Cyril Fournier

  6. INSERM UMR1141, Université de Paris, Paris, France

    Alain Verloes

  7. Genetics Department, AP-HP Nord, Robert-Debré University Hospital, Paris, France

    Alain Verloes

  8. Centre de Référence maladies rares « maladies dermatologiques en mosaïque », service de dermatologie, FHU-TRANSLAD, Dijon University Hospital, Dijon, France

    Pierre Vabres

  9. Service Dermatologie, Dijon University Hospital, Dijon, France

    Pierre Vabres & Orlane Prevel

  10. Centre de Référence maladies rares « Anomalies du développement et syndromes malformatifs », centre de génétique, FHU-TRANSLAD, Dijon University Hospital, Dijon, France

    Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Hana Safraou & Laurence Faivre

  11. Centre de Référence maladies rares « Déficiences intellectuelles de cause rare », centre de génétique, FHU-TRANSLAD, Dijon University Hospital, Dijon, France

    Frédéric Tran Mau-Them & Christel Thauvin-Robinet

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  1. Philippine Garret
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Contributions

PG, MC and YD designed the study. PG, MC, AnV, SV, ET, CP, ALB, FTMT, HS, CTR, LF and YD analyzed the data. PG and MC performed PCR and MiSeq sequencing. MC performed cell cultures and experiments. AlV, PV, OP, ASDP, CTR, LF performed clinical analysis. All authors contributed to read, and approved the final version of the paper.

Corresponding author

Correspondence to Philippine Garret.

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The study was approved by the ethics committee of the Dijon University Hospital. Informed consents were provided for the study, with separate consent obtained for the use of photographs.

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Garret, P., Chevarin, M., Vitobello, A. et al. A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort. Eur J Hum Genet 31, 761–768 (2023). https://doi.org/10.1038/s41431-022-01250-3

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