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Original research
The clinical relevance of intragenic NRXN1 deletions
  1. Nele Cosemans1,2,
  2. Laura Vandenhove1,
  3. Annick Vogels1,
  4. Koenraad Devriendt1,
  5. Hilde Van Esch1,
  6. Griet Van Buggenhout1,
  7. Hilde Olivié3,
  8. Thomy de Ravel1,
  9. Els Ortibus3,4,
  10. Eric Legius1,2,
  11. Peter Aerssens5,
  12. Jeroen Breckpot1,
  13. Joris R. Vermeesch1,
  14. Sanbing Shen6,
  15. Jacqueline Fitzgerald7,
  16. Louise Gallagher7,
  17. Hilde Peeters1,2
  1. 1 Department of Human Genetics, KU Leuven, Leuven, Belgium
  2. 2 Leuven Autism Research (LAuRes), KU Leuven, Leuven, Belgium
  3. 3 Center for Developmental Disabilities Leuven, Leuven, Belgium
  4. 4 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  5. 5 Pediatric Department, Jessa Hospital, Hasselt, Belgium
  6. 6 Regenerative Medicine Institute, School of Medicine, BioMedical Sciences Building, National University of Ireland (NUI), Galway, Ireland
  7. 7 Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
  1. Correspondence to Professor Hilde Peeters, Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven 3000, Belgium; hilde.peeters{at}


Background Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided.

Methods The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions.

Results The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6–24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1–5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions.

Conclusion Exon 6–24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1–5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.

  • genotype-phenotype correlation
  • neuropsychiatric disorders
  • intellectual disability
  • susceptibility variant
  • prevalence

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  • Contributors NC performed the literature case review, assembled the literature database, did the hypothesis testing, analysed the exact breakpoints in the Leuven cohort, assembled all information in an interactive table, drafted and submitted the manuscript. LV performed the experiments for exact breakpoint analysis in the Leuven cohort. AV, KD, HVE, GVB, HO, TJLdR, EO, EL, PA and JB established the Leuven cohort: providing clinical cases, DNA samples and clinical information. JRV and EL were responsible for the array CGH in the Leuven cohort and proofreading. SS, JF, LG and HP conceptualised the subject in an international collaboration and performed proofreading. HP was responsible for the conceptualisation of the subject, study design, clinical literature case review and drafting the manuscript.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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