HGG Advances (Apr 2024)
Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features
- Morad Ansari,
- Kamli N.W. Faour,
- Akiko Shimamura,
- Graeme Grimes,
- Emeline M. Kao,
- Erica R. Denhoff,
- Ana Blatnik,
- Daniel Ben-Isvy,
- Lily Wang,
- Benjamin M. Helm,
- Helen Firth,
- Amy M. Breman,
- Emilia K. Bijlsma,
- Aiko Iwata-Otsubo,
- Thomy J.L. de Ravel,
- Vincent Fusaro,
- Alan Fryer,
- Keith Nykamp,
- Lara G. Stühn,
- Tobias B. Haack,
- G. Christoph Korenke,
- Panayiotis Constantinou,
- Kinga M. Bujakowska,
- Karen J. Low,
- Emily Place,
- Jennifer Humberson,
- Melanie P. Napier,
- Jessica Hoffman,
- Jane Juusola,
- Matthew A. Deardorff,
- Wanqing Shao,
- Shira Rockowitz,
- Ian Krantz,
- Maninder Kaur,
- Sarah Raible,
- Victoria Dortenzio,
- Sabine Kliesch,
- Moriel Singer-Berk,
- Emily Groopman,
- Stephanie DiTroia,
- Sonia Ballal,
- Siddharth Srivastava,
- Kathrin Rothfelder,
- Saskia Biskup,
- Jessica Rzasa,
- Jennifer Kerkhof,
- Haley McConkey,
- Bekim Sadikovic,
- Sarah Hilton,
- Siddharth Banka,
- Frank Tüttelmann,
- Donald F. Conrad,
- Anne O’Donnell-Luria,
- Michael E. Talkowski,
- David R. FitzPatrick,
- Philip M. Boone
Affiliations
- Morad Ansari
- South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Kamli N.W. Faour
- Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children’s Hospital, Boston, MA, USA
- Akiko Shimamura
- Division of Hematology and Oncology, Boston Children’s Hospital, Boston, MA, USA
- Graeme Grimes
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Emeline M. Kao
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA
- Erica R. Denhoff
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA
- Ana Blatnik
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Daniel Ben-Isvy
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
- Lily Wang
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
- Benjamin M. Helm
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Helen Firth
- Clinical Genetics, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
- Amy M. Breman
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Emilia K. Bijlsma
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
- Aiko Iwata-Otsubo
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Thomy J.L. de Ravel
- Centre for Human Genetics, UZ Leuven/Leuven University Hospitals, Leuven, Belgium
- Vincent Fusaro
- Invitae, San Francisco, CA, USA
- Alan Fryer
- Department of Clinical Genetics, Alder Hey Children’s Hospital Liverpool, Liverpool, UK
- Keith Nykamp
- Invitae, San Francisco, CA, USA
- Lara G. Stühn
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- Tobias B. Haack
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- G. Christoph Korenke
- Department of Neuropaediatric and Metabolic Diseases, University Children’s Hospital Oldenburg, Oldenburg, Germany
- Panayiotis Constantinou
- West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK
- Kinga M. Bujakowska
- Massachusetts Eye and Ear Infirmary, Boston, MA, USA
- Karen J. Low
- University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; University of Bristol, Bristol, UK
- Emily Place
- Massachusetts Eye and Ear Infirmary, Boston, MA, USA
- Jennifer Humberson
- University of Virginia Health System, Charlottesville, VA, USA
- Melanie P. Napier
- GeneDx, Gaithersburg, MD, USA
- Jessica Hoffman
- GeneDx, Gaithersburg, MD, USA
- Jane Juusola
- GeneDx, Gaithersburg, MD, USA
- Matthew A. Deardorff
- Departments of Pathology and Pediatrics, Children’s Hospital Los Angeles and University of Southern California, Los Angeles, CA, USA
- Wanqing Shao
- Research Computing, Information Technology, Boston Children’s Hospital, Boston, MA, USA
- Shira Rockowitz
- Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Research Computing, Information Technology, Boston Children’s Hospital, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA
- Ian Krantz
- Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Maninder Kaur
- Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Sarah Raible
- Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Victoria Dortenzio
- Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Sabine Kliesch
- Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany
- Moriel Singer-Berk
- Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Emily Groopman
- Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stephanie DiTroia
- Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Sonia Ballal
- Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children’s Hospital, Boston, MA, USA; Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA
- Siddharth Srivastava
- Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children’s Hospital, Boston, MA, USA; Divison of Neurology, Boston Children’s Hospital, Boston, MA, USA
- Kathrin Rothfelder
- Zentrum für Humangenetik, Tübingen, Germany
- Saskia Biskup
- Zentrum für Humangenetik, Tübingen, Germany; Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany
- Jessica Rzasa
- Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Jennifer Kerkhof
- Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Haley McConkey
- Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Bekim Sadikovic
- Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Sarah Hilton
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
- Siddharth Banka
- 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, University of Manchester, Manchester, UK
- Frank Tüttelmann
- Institute of Reproductive Genetics, University of Münster, Münster, Germany
- Donald F. Conrad
- Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR, USA; Center for Embryonic Cell and Gene Therapy, Oregon Health and Science University, Portland, OR, USA
- Anne O’Donnell-Luria
- Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Michael E. Talkowski
- Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- David R. FitzPatrick
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Philip M. Boone
- Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children’s Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Corresponding author
- Journal volume & issue
-
Vol. 5,
no. 2
p. 100273
Abstract
Summary: 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 multilayered genomic data paired with careful phenotyping.
