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  • Splice site variants in the canonical donor site of MED13L exon 7 lead to intron retention in patients with MED13L syndrome

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Neurogenetics
Short report
Splice site variants in the canonical donor site of MED13L exon 7 lead to intron retention in patients with MED13L syndrome
  1. Jade Fauqueux1,
  2. Simon Boussion1,2,
  3. Caroline Thuillier3,
  4. Evine Meurisse1,
  5. Didier Lacombe4,5,
  6. Marjolaine Willems6,7,
  7. Amélie Piton8,9,
  8. Emilie Ait-Yahya10,
  9. Jamal Ghoumid1,2,
  10. Thomas Smol1,3
  1. 1Univ. Lille, ULR7364 RADEME, Lille, France
  2. 2CHU Lille, Clinique de Génétique, Lille, France
  3. 3CHU Lille, Institut de Génétique Médicale, Lille, France
  4. 4Univ. Bordeaux, UMR1211 – MRGM – Maladies Rares Génétique et Métabolisme, Bordeaux, France
  5. 5CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France
  6. 6CHU Montpellier, Département de Génétique Médicale, Centre de Référence Anomalies du Développement, Montpellier, France
  7. 7Univ. Montpellier, Inserm, Institute for Neurosciences of Montpellier, Montpellier, France
  8. 8IGBMC, Neurogenetics and Translational Medicine, Illkirch-Graffenstaden, France
  9. 9CHU Strasbourg, Laboratoire de Diagnostic Génétique, Strasbourg, France
  10. 10CHU Lille, Unité de Bio-informatique, Plateau de Biologie-Moléculaire, Lille, France
  1. Correspondence to Dr Thomas Smol, Institut de Génétique Médicale, CHU de Lille, Lille, France; thomas.smol{at}chu-lille.fr

Abstract

Pathogenic variants in the MED13L gene are associated with the autosomal dominant MED13L syndrome, which is characterised by global developmental delay and cardiac malformations. We investigated two heterozygous MED13L variants located at the canonical donor splice site motif of exon 7: c.1009+1G>C and c.1009+5G>C. We report that in silico predictions suggested two possible outcomes: exon 7 skipping, resulting in loss of the phosphodegron motif essential for MED13L regulation, or activation of a cryptic donor site in intron 7, leading to intron retention. RNA analysis confirmed that both variants affected the exon 7 splice donor site, resulting in the retention of 73 bp of intron 7. This retention caused a frameshift and premature translation termination, consistent with haploinsufficiency. Our results highlight the importance of combining predictive and experimental approaches to understand the functional impact of splice site variants. These insights into the molecular consequences of MED13L variants provide a deeper understanding of the genetic basis of MED13L syndrome.

  • RNA Splicing
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA

https://doi.org/10.1136/jmg-2024-110154

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    Footnotes

    • Contributors JF and TS wrote the manuscript. JF, EM and CT performed the RNA experiments. SB, AP and TS performed the data sequencing interpretation. EA-Y and AP performed the bioinformatics analysis. DL, MW and JG collected and evaluated the clinical and genetic data. TS and JG revised the manuscript. All authors discussed the results, commented on the manuscript and approved the final manuscript. TS is the guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.