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

January 30, 2024

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

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 14 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 an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features 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.

Update of: PMID: 37808847

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