Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Dmitrijs Rots; Eric Chater-Diehl; Alexander J M Dingemans; Sarah J Goodman; Michelle T Siu; Cheryl Cytrynbaum; Sanaa Choufani; Ny Hoang; Susan Walker; Zain Awamleh; Joshua Charkow; Stephen Meyn; Rolph Pfundt; Tuula Rinne; Thatjana Gardeitchik; Bert B A de Vries; A Chantal Deden; Erika Leenders; Michael Kwint; Constance T R M Stumpel; Servi J C Stevens; Jeroen R Vermeulen; Jeske V T van Harssel; Danielle G M Bosch; Koen L I van Gassen; Ellen van Binsbergen; Christa M de Geus; Hein Brackel; Maja Hempel; Davor Lessel; Jonas Denecke; Anne Slavotinek; Jonathan Strober; Amy Crunk; Leandra Folk; Ingrid M Wentzensen; Hui Yang; Fanggeng Zou; Francisca Millan; Richard Person; Yili Xie; Shuxi Liu; Lilian B Ousager; Martin Larsen; Laura Schultz-Rogers; Eva Morava; Eric W Klee; Ian R Berry; Jennifer Campbell; Kristin Lindstrom; Brianna Pruniski; Ann M Neumeyer; Jessica A Radley; Chanika Phornphutkul; Berkley Schmidt; William G Wilson; Katrin Õunap; Karit Reinson; Sander Pajusalu; Arie van Haeringen; Claudia Ruivenkamp; Roos Cuperus; Fernando Santos-Simarro; María Palomares-Bralo; Marta Pacio-Míguez; Alyssa Ritter; Elizabeth Bhoj; Elin Tønne; Kristian Tveten; Gerarda Cappuccio; Nicola Brunetti-Pierri; Leah Rowe; Jason Bunn; Margarita Saenz; Konrad Platzer; Mareike Mertens; Oana Caluseriu; Małgorzata J M Nowaczyk; Ronald D Cohn; Peter Kannu; Ebba Alkhunaizi; David Chitayat; Stephen W Scherer; Han G Brunner; Lisenka E L M Vissers; Tjitske Kleefstra; David A Koolen; Rosanna Weksberg

doi:10.1016/j.ajhg.2021.04.008

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Am J Hum Genet. 2021 Jun 3;108(6):1053-1068. doi: 10.1016/j.ajhg.2021.04.008. Epub 2021 Apr 27.

Authors

Dmitrijs Rots¹, Eric Chater-Diehl², Alexander J M Dingemans¹, Sarah J Goodman², Michelle T Siu², Cheryl Cytrynbaum³, Sanaa Choufani², Ny Hoang⁴, Susan Walker², Zain Awamleh², Joshua Charkow², Stephen Meyn², Rolph Pfundt⁵, Tuula Rinne⁵, Thatjana Gardeitchik⁵, Bert B A de Vries¹, A Chantal Deden⁵, Erika Leenders⁵, Michael Kwint⁵, Constance T R M Stumpel⁶, Servi J C Stevens⁷, Jeroen R Vermeulen⁷, Jeske V T van Harssel⁸, Danielle G M Bosch⁸, Koen L I van Gassen⁸, Ellen van Binsbergen⁸, Christa M de Geus⁹, Hein Brackel¹⁰, Maja Hempel¹¹, Davor Lessel¹¹, Jonas Denecke¹², Anne Slavotinek¹³, Jonathan Strober¹⁴, Amy Crunk¹⁵, Leandra Folk¹⁵, Ingrid M Wentzensen¹⁵, Hui Yang¹⁵, Fanggeng Zou¹⁵, Francisca Millan¹⁵, Richard Person¹⁵, Yili Xie¹⁵, Shuxi Liu¹⁵, Lilian B Ousager¹⁶, Martin Larsen¹⁶, Laura Schultz-Rogers¹⁷, Eva Morava¹⁷, Eric W Klee¹⁸, Ian R Berry¹⁹, Jennifer Campbell²⁰, Kristin Lindstrom²¹, Brianna Pruniski²¹, Ann M Neumeyer²², Jessica A Radley²³, Chanika Phornphutkul²⁴, Berkley Schmidt²⁵, William G Wilson²⁵, Katrin Õunap²⁶, Karit Reinson²⁶, Sander Pajusalu²⁶, Arie van Haeringen²⁷, Claudia Ruivenkamp²⁷, Roos Cuperus²⁸, Fernando Santos-Simarro²⁹, María Palomares-Bralo²⁹, Marta Pacio-Míguez²⁹, Alyssa Ritter³⁰, Elizabeth Bhoj³⁰, Elin Tønne³¹, Kristian Tveten³², Gerarda Cappuccio³³, Nicola Brunetti-Pierri³³, Leah Rowe³⁴, Jason Bunn³⁴, Margarita Saenz³⁴, Konrad Platzer³⁵, Mareike Mertens³⁵, Oana Caluseriu³⁶, Małgorzata J M Nowaczyk³⁷, Ronald D Cohn³⁸, Peter Kannu³⁹, Ebba Alkhunaizi⁴⁰, David Chitayat⁴¹, Stephen W Scherer⁴², Han G Brunner⁴³, Lisenka E L M Vissers¹, Tjitske Kleefstra¹, David A Koolen⁴⁴, Rosanna Weksberg⁴⁵

Affiliations

¹ 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.
² Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ 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.
⁴ 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.
⁵ Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
⁶ Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.
⁷ Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.
⁸ Department of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.
⁹ University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
¹⁰ Catharina Hospital, 5623 EJ Eindhoven, the Netherlands.
¹¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
¹² Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
¹³ Division of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94143, USA.
¹⁴ Division of Child Neurology, Department of Neurology & Pediatrics, UCSF, San Francisco, CA 94143, USA.
¹⁵ GeneDx, Gaithersburg, MD 20877, USA.
¹⁶ Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark.
¹⁷ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.
¹⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA.
¹⁹ Yorkshire and North East Genomic Laboratory Hub Central Laboratory, Leeds LS1 3EX, UK.
²⁰ Department of Clinical Genetics, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
²¹ Phoenix Children's Hospital, Phoenix, AZ 85016 USA.
²² Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
²³ 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.
²⁴ Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
²⁵ University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
²⁶ 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.
²⁷ Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
²⁸ Department of Paediatrics, Juliana Children's Hospital HAGA, 2545 AA the Hague, the Netherlands.
²⁹ Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.
³⁰ Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
³¹ Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway.
³² Department of Medical genetics, Telemark Hospital Trust, 3710 Skien, Norway.
³³ Department of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy.
³⁴ University of Colorado School of Medicine, Aurora, CO 13001, USA.
³⁵ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
³⁶ Department of Medical Genetics in the Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
³⁷ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
³⁸ 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.
³⁹ Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
⁴⁰ Genetics Program, North York General Hospital, Toronto, ON M2K 1E1, Canada.
⁴¹ 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.
⁴² 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.
⁴³ 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.
⁴⁴ 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: [email protected].
⁴⁵ 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: [email protected].

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.

Keywords: DNA methylation signature; Floating-Harbor syndrome; SRCAP; epigenomics; genotype-phenotype correlation; intellectual disability; neurodevelopmental disorders; non-FLHS SRCAP-related NDD; nonsense-mediated decay; speech delay.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics
Abnormalities, Multiple / pathology*
Adenosine Triphosphatases / genetics*
Case-Control Studies
Cohort Studies
Craniofacial Abnormalities / genetics
Craniofacial Abnormalities / pathology*
DNA Methylation*
Epigenesis, Genetic*
Female
Genetic Predisposition to Disease
Growth Disorders / genetics
Growth Disorders / pathology*
Heart Septal Defects, Ventricular / genetics
Heart Septal Defects, Ventricular / pathology*
Humans
Infant, Newborn
Male
Mutation*
Neurodevelopmental Disorders / genetics
Neurodevelopmental Disorders / pathology*
Phenotype*

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Authors

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Abstract

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