Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature
The American Journal of Human Genetics, vol. 108, pp. 1053–1068
Abstract
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
Authors 87
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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University of Toronto · Hospital for Sick Children
Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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University of Toronto · Hospital for Sick Children
Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Medical Center
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Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Maastricht University Medical Centre · Maastricht University
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Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands
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Maastricht University Medical Centre · Maastricht University
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Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands
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Maastricht University Medical Centre · Maastricht University
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Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands
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Utrecht University · University Medical Center Utrecht
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Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands
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Utrecht University · University Medical Center Utrecht
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Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands
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Utrecht University · University Medical Center Utrecht
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Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands
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Utrecht University · University Medical Center Utrecht
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Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands
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University Medical Center Groningen · University of Groningen
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University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
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Catharina Hospital, 5623 EJ Eindhoven, the Netherlands
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University Medical Center Hamburg-Eppendorf
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Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
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Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
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Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
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University of California, San Francisco
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Division of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94143, USA
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University of California, San Francisco
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Division of Child Neurology, Department of Neurology & Pediatrics, UCSF, San Francisco, CA 94143, USA
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GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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Affiliation as printed
GeneDx, Gaithersburg, MD 20877, USA
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University of Southern Denmark · Odense University Hospital
Affiliation as printed
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark
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University of Southern Denmark · Odense University Hospital
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Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark
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Affiliation as printed
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA
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Affiliation as printed
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA
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Affiliation as printed
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA
Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA
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Affiliation as printed
Yorkshire and North East Genomic Laboratory Hub Central Laboratory, Leeds LS1 3EX, UK
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Department of Clinical Genetics, Chapel Allerton Hospital, Leeds LS7 4SA, UK
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Affiliation as printed
Phoenix Children's Hospital, Phoenix, AZ 85016 USA
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Affiliation as printed
Phoenix Children's Hospital, Phoenix, AZ 85016 USA
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Harvard University · Massachusetts General Hospital
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Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA
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London North West Healthcare NHS Trust · Birmingham Women's Hospital · Birmingham Women’s and Children’s NHS Foundation Trust
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Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK; Clinical Genetics, London North West University Healthcare Foundation Trust, London HA1 3UJ, UK
Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK
Clinical Genetics, London North West University Healthcare Foundation Trust, London HA1 3UJ, UK
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Affiliation as printed
Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
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Affiliation as printed
University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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Affiliation as printed
University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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Tartu University Hospital · University of Tartu
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Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia
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Tartu University Hospital · University of Tartu
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Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia
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Tartu University Hospital · University of Tartu
Affiliation as printed
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406 Tartu, Estonia
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Leiden University Medical Center
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Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
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Leiden University Medical Center
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Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
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Affiliation as printed
Department of Paediatrics, Juliana Children's Hospital HAGA, 2545 AA the Hague, the Netherlands
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases
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Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases
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Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases
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Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain
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Children's Hospital of Philadelphia
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Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA
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Children's Hospital of Philadelphia
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Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA
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Affiliation as printed
Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway
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Affiliation as printed
Department of Medical genetics, Telemark Hospital Trust, 3710 Skien, Norway
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Telethon Institute Of Genetics And Medicine · University of Naples Federico II
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Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy
Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy
Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy
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Telethon Institute Of Genetics And Medicine · University of Naples Federico II
Affiliation as printed
Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy
Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy
Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy
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University of Colorado Anschutz
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University of Colorado School of Medicine, Aurora, CO 13001, USA
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University of Colorado Anschutz
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University of Colorado School of Medicine, Aurora, CO 13001, USA
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University Hospital Leipzig · Leipzig University
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Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
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University Hospital Leipzig · Leipzig University
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Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
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Affiliation as printed
Department of Medical Genetics in the Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
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Affiliation as printed
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
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University of Toronto · Hospital for Sick Children
Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Affiliation as printed
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada
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Affiliation as printed
Genetics Program, North York General Hospital, Toronto, ON M2K 1E1, Canada
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Mount Sinai Hospital · University of Toronto · Hospital for Sick Children
Affiliation as printed
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
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University of Toronto · Hospital for Sick Children
Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Radboud University Nijmegen · Maastricht University Medical Centre · Radboud University Medical Center · Maastricht University · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands; Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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David A. Koolen corresponding
Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands. Electronic address: david.koolen@radboudumc.nl
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands
Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands
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Rosanna Weksberg corresponding
University of Toronto · Hospital for Sick Children
Affiliation as printed
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada; Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON M5S 2Z9, Canada. Electronic address: rweksb@sickkids.ca
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada
Department of Pediatrics, University of Toronto, Toronto, ON M5G 1V7, Canada
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON M5S 2Z9, Canada
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