Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Schaida Schirwani^{1

2}, Shadi Albaba³, Deanna Alexis Carere⁴, Maria J Guillen Sacoto⁴, Francisca Milan Zamora⁴, Yue Si⁴, Rachel Rabin⁵, John Pappas⁵, Deborah L Renaud⁶, Natalie Hauser⁷, Evan Reid⁸, Patricia Blanchet⁹, Nichola Foulds^{10

11}, Abhijit Dixit¹², Richard Fisher¹³, Ruth Armstrong¹⁴, Bertrand Isidor¹⁵, Benjamin Cogne¹⁵, Samantha Schrier Vergano¹⁶, Serwet Demirdas¹⁷, Natalie Dykzeul¹⁸, Julie S Cohen^{19

20}, Katheryn Grand²¹, Dayna Morel²², Anne Slavotinek²³, Hessa F Albassam²⁴, Swati Naik²⁵, John Dean²⁶, Nicola Ragge²⁵, Cinzia Costa²⁷, Maria Giovanna Tedesco^{28

29}, Rachel E Harrison¹², Arjan Bouman¹⁷, Emily Palen³⁰, Thomas D Challman³⁰, Marjolein H Willemsen³¹, Julie Vogt²⁵, Christopher Cunniff³², Katherine Bergstrom³², Jagdeep S Walia³³, Ange-Line Bruel³⁴, Usha Kini³⁵, Fowzan S Alkuraya³⁶, Valerie Slegesky³⁷, Naomi Meeks³⁷, Paula Girotto³⁸, Diana Johnson^{1

39}; DDD Study⁴⁰; Ruth Newbury-Ecob⁴¹, Charlotte W Ockeloen³¹, Paolo Prontera²⁸, Sally Ann Lynch⁴², Dong Li⁴³, John M Graham Jr⁴⁴, Tyler Mark Pierson⁴⁵, Meena Balasubramanian^{1

2}

Affiliations

¹ Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
² Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
³ Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁴ GeneDx, Inc, Gaithersburg, Maryland, USA.
⁵ Department of Pediatrics, New York University School of Medicine, New York, New York, USA.
⁶ Division of Child and Adolescent Neurology, Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Department of Pediatrics, Division of Medical Genomics, Inova Health System, Falls Church, Virginia, USA.
⁸ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
⁹ Département de Génétique Médicale, CHU de Montpellier, Montpellier, France.
¹⁰ Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹¹ Faculty of Medicine, University of Southampton, Southampton, UK.
¹² Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹³ Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK.
¹⁴ Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁵ Service de génétique médicale, CHU Nantes, Nantes, France.
¹⁶ Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Eastern Virginia Medical School, Norfolk, Virginia, USA.
¹⁷ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁸ Lucile Packard Children's Hospital, Stanford Children's Health, Palo Alto, California, USA.
¹⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
²⁰ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
²² University of Miami, Miller School of Medicine, Miami, Florida, USA.
²³ Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, California, USA.
²⁴ Department of Pediatrics, Care National Hospital, Riyadh, Saudi Arabia.
²⁵ West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK.
²⁶ Clinical Genetics Service, NHS Grampian, Aberdeen Royal Infirmary, Aberdeen, UK.
²⁷ Neurology Clinic, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
²⁸ Medical Genetics Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
²⁹ Genetics Unit, "Mauro Baschirotto" Institute for Rare Diseases (B.I.R.D.), Costozza di Longare, Vicenza, Italy.
³⁰ Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
³¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
³² Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
³³ Divsion of Medical Genetics, Departments of Pediatrics, Queen's University, Kingston, Ontario, Canada.
³⁴ UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
³⁵ Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
³⁶ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
³⁷ University of Colorado & Children's Hospital Colorado, Denver, Colorado, USA.
³⁸ Division of Child Neurology, Department of Pediatrics, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil.
³⁹ EDS National Diagnostic Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁴⁰ Welcome Trust Sanger Institute, Cambridge, UK.
⁴¹ Bristol Regional Genetics Service, St Michael's Hospital, Bristol, UK.
⁴² Department of Clinical Genetics, Temple Street Children's Hospital, Dublin, Ireland.
⁴³ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴⁴ Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁴⁵ Departments of Pediatrics, Neurology, Cedars-Sinai Center for the Undiagnosed Patient, and Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA.

PMID: 34436830
DOI: 10.1002/ajmg.a.62465

Free article

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Schaida Schirwani et al. Am J Med Genet A. 2021 Nov.

Free article

. 2021 Nov;185(11):3446-3458.

doi: 10.1002/ajmg.a.62465. Epub 2021 Aug 26.

Authors

Affiliations

¹ Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
² Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
³ Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁴ GeneDx, Inc, Gaithersburg, Maryland, USA.
⁵ Department of Pediatrics, New York University School of Medicine, New York, New York, USA.
⁶ Division of Child and Adolescent Neurology, Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Department of Pediatrics, Division of Medical Genomics, Inova Health System, Falls Church, Virginia, USA.
⁸ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
⁹ Département de Génétique Médicale, CHU de Montpellier, Montpellier, France.
¹⁰ Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹¹ Faculty of Medicine, University of Southampton, Southampton, UK.
¹² Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹³ Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK.
¹⁴ Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁵ Service de génétique médicale, CHU Nantes, Nantes, France.
¹⁶ Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Eastern Virginia Medical School, Norfolk, Virginia, USA.
¹⁷ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁸ Lucile Packard Children's Hospital, Stanford Children's Health, Palo Alto, California, USA.
¹⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
²⁰ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
²² University of Miami, Miller School of Medicine, Miami, Florida, USA.
²³ Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, California, USA.
²⁴ Department of Pediatrics, Care National Hospital, Riyadh, Saudi Arabia.
²⁵ West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK.
²⁶ Clinical Genetics Service, NHS Grampian, Aberdeen Royal Infirmary, Aberdeen, UK.
²⁷ Neurology Clinic, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
²⁸ Medical Genetics Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
²⁹ Genetics Unit, "Mauro Baschirotto" Institute for Rare Diseases (B.I.R.D.), Costozza di Longare, Vicenza, Italy.
³⁰ Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
³¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
³² Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
³³ Divsion of Medical Genetics, Departments of Pediatrics, Queen's University, Kingston, Ontario, Canada.
³⁴ UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
³⁵ Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
³⁶ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
³⁷ University of Colorado & Children's Hospital Colorado, Denver, Colorado, USA.
³⁸ Division of Child Neurology, Department of Pediatrics, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil.
³⁹ EDS National Diagnostic Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁴⁰ Welcome Trust Sanger Institute, Cambridge, UK.
⁴¹ Bristol Regional Genetics Service, St Michael's Hospital, Bristol, UK.
⁴² Department of Clinical Genetics, Temple Street Children's Hospital, Dublin, Ireland.
⁴³ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴⁴ Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁴⁵ Departments of Pediatrics, Neurology, Cedars-Sinai Center for the Undiagnosed Patient, and Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA.

PMID: 34436830
DOI: 10.1002/ajmg.a.62465

Erratum in

Expanding the phenotype of ASXL3-related syndrome: a comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3. Am J Med Genet A. 2021;185A(11):3446-3458. Doi:10.1002/ajmg.a.62465″.
[No authors listed] [No authors listed] Am J Med Genet A. 2023 Jan;191(1):310. doi: 10.1002/ajmg.a.62993. Epub 2022 Oct 12. Am J Med Genet A. 2023. PMID: 36222436 No abstract available.

Abstract

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Keywords: ASXL3; ASXL3-related syndrome; BRPS; Bainbridge-Ropers syndrome; intellectual disability; speech impairment.

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References

REFERENCES

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Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Affiliations

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Authors

Affiliations

Erratum in

Abstract

References

REFERENCES

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases