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Genotype-phenotype correlations
Original research
ATR-16 syndrome: mechanisms linking monosomy to phenotype
  1. Christian Babbs1,
  2. Jill Brown1,
  3. Sharon W Horsley1,
  4. Joanne Slater1,
  5. Evie Maifoshie1,
  6. Shiwangini Kumar2,
  7. Paul Ooijevaar3,
  8. Marjolein Kriek3,
  9. Amanda Dixon-McIver2,
  10. Cornelis L Harteveld3,
  11. Jan Traeger-Synodinos4,
  12. Andrew O M Wilkie5,6,
  13. Douglas R Higgs1,
  14. Veronica J Buckle1
  1. 1 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  2. 2 IGENZ Ltd, Auckland, New Zealand
  3. 3 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  4. 4 Department of Medical Genetics, National and Kapodistrian University of Athens, Athens, Greece
  5. 5 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  6. 6 Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
  1. Correspondence to Dr Christian Babbs, MRC MHU, MRC WIMM, University of Oxford, Oxford, UK; christian.babbs{at}imm.ox.ac.uk; Professor Veronica J Buckle, MRC MHU, MRC WIMM, University of Oxford, Oxford, UK; veronica.buckle{at}imm.ox.ac.uk

Abstract

Background Deletions removing 100s–1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.

Methods Here, as an example of this common phenomenon, we analysed 41 patients with simple deletions of ~177 to ~2000 kb affecting one allele of the well-characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised deletion extents and screened for genetic background effects, telomere position effect and compensatory upregulation of hemizygous genes.

Results We find the risk of developmental and neurological abnormalities arises from much smaller distal chromosome 16 deletions (~400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes; however, genetic background effects substantially modify phenotypic abnormalities.

Conclusions Using ATR-16 as a general model of disorders caused by CNVs, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.

  • ATR16
  • thalassemia
  • CNV
  • developmental delay
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jmedgenet-2019-106528

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    Footnotes

    • Contributors DRH and VJB conceived the project. CB, VJB and DRH wrote the paper. CB, JS, CLH, JB, EM, SWH, VJB, SK and AD-M performed experimental work. JT-S, PO, MK, AD-M and AOMW assessed patients and clinical data. All authors commented on the manuscript.

    • Funding This work was supported by the Medical Research Council grant number: (MC_uu_12009).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by the NRES Committee North West, Haydock, HRA NRES Centre, Manchester under the title ‘Establishing the molecular basis for atypical forms of thalassaemia’ (reference number MREC: 03/8/097) with written consent from patients and/or parents.

    • 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.