Heterozygous loss-of-function SMC3 variants are associated with variable and incompletely penetrant growth and developmental features

September 28, 2023

Morad Ansari 1 2 3, Kamli N W Faour 4 5 3, Akiko Shimamura 6, Graeme Grimes 2, Emeline M Kao 7, Erica R Denhoff 7, Ana Blatnik 2 8, Daniel Ben-Isvy 9 10 11, Lily Wang 9 10 11, Benjamin M Helm 12, Helen Firth 13, Amy M Breman 12, Emilia K Bijlsma 14, Aiko Iwata-Otsubo 12, Thomy J L de Ravel 15, Vincent Fusaro 16, Alan Fryer 17, Keith Nykamp 16, Lara G Stühn 18, Tobias B Haack 18, G Christoph Korenke 19, Panayiotis Constantinou 20, Kinga M Bujakowska 21, Karen J Low 22 23, Emily Place 21, Jennifer Humberson 24, Melanie P Napier 25, Jessica Hoffman 25, Jane Juusola 25, Matthew A Deardorff 26, Wanqing Shao 27, Shira Rockowitz 27 28 4, Ian Krantz 29, Maninder Kaur 29, Sarah Raible 29, Sabine Kliesch 30, Moriel Singer-Berk 10, Emily Groopman 4 10, Stephanie DiTroia 10, Sonia Ballal 5 31, Siddharth Srivastava 5 32, Kathrin Rothfelder 33, Saskia Biskup 33 34, Jessica Rzasa 35, Jennifer Kerkhof 35, Haley McConkey 35, Anne O’Donnell-Luria 4 9 10, Bekim Sadikovic 35, Sarah Hilton 36, Siddharth Banka 36, Frank Tüttelmann 37, Donald Conrad 38 39, Michael E Talkowski 10 9, David R FitzPatrick 2 3, Philip M Boone 5 4 9 10 3

Abstract

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 13 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links to SMC3 including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest that SMC3 pLoF variants reduce SMC3 expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature of SMC3 loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multi-layered genomic data paired with careful phenotyping.

Keywords: CdLS3; Cornelia de Lange syndrome; LoF; SMC3; cohesin; loss-of-function.

  1. South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK.
  2. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  3. These authors contributed equally.
  4. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, US.
  5. Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children’s Hospital, Boston, MA, US.
  6. Division of Hematology and Oncology, Boston Children’s Hospital, Boston, MA, US.
  7. Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, US.
  8. Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, SI.
  9. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US.
  10. Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, US.
  11. Division of Medical Sciences, Harvard Medical School, Boston, MA, US.
  12. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, US.
  13. Clinical Genetics, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK.
  14. Department of Clinical Genetics, Leiden University Medical Centre, Leiden, NL.
  15. Centre for Human Genetics, UZ Leuven/ Leuven University Hospitals, Leuven, BE.
  16. Invitae, San Francisco, CA, US.
  17. Department of Clinical Genetics, Alder Hey Children’s Hospital Liverpool, Liverpool, UK.
  18. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, DE.
  19. University Children’s Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, University Children’s Hospital Oldenburg, Oldenburg, DE.
  20. West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK.
  21. Massachusetts Eye and Ear Infirmary, Boston, MA, US.
  22. University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
  23. University of Bristol, Bristol, UK.
  24. University of Virginia Health System, Charlottesville, VA, US.
  25. GeneDx, Gaithersburg, MD, US.
  26. Departments of Pathology and Pediatrics, Children’s Hospital Los Angeles and University of Southern California, Los Angeles, CA, US.
  27. Research Computing, Information Technology, Boston Children’s Hospital, Boston, MA, US.
  28. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, US.
  29. Children’s Hospital of Philadelphia, Philadelphia, PA, US.
  30. Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster, DE.
  31. Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, US.
  32. Divison of Neurology, Boston Children’s Hospital, Boston, MA, US.
  33. Zentrum für Humangenetik, Tübingen, DE.
  34. Center for Genomics and Transcriptomics (CeGaT), Tübingen, DE.
  35. Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, LHSC, London, CA.
  36. Manchester University, Manchester, UK.
  37. Institute of Reproductive Genetics, University of Münster, Münster, DE.
  38. Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR, US.
  39. Center for Embryonic Cell and Gene Therapy, Oregon Health and Science University, Portland, OR, US.