ArticleAmerican journal of human genetics2021
Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 67 citations in OpenAlex.
- Biallelic inactivating variants in the chromatin remodeler DMAP1 cause a syndromic neurodevelopmental disorder.The Journal of clinical investigation · 2026Article
- Genotypic and Phenotypic Profile of 50 Cases With Chromatin Remodeling Complexes-Related Neurological Disorders.CNS neuroscience & therapeutics · 2026Article
- Pediatric floating-harbor syndrome: clinical features and treatment outcomes in a cohort of Chinese children.European journal of pediatrics · 2026Article
- Autism Spectrum Disorder in a Child with Floating-Harbor Syndrome: A Case Report.Noro psikiyatri arsivi · 2026Article
- Polydactyly and syndactyly in a Chinese family with Floating-Harbor syndrome: an expansion of the clinical phenotype.Frontiers in genetics · 2026Article
- Identification of Novel Co-OccurringThe application of clinical genetics · 2026Article
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- Scalable screening of ternary-code DNA methylation dynamics associated with human traits.Cell genomics · 2025Article
- [Clinical and molecular genetic features of cases of Floating-Harbor syndrome].Problemy endokrinologii · 2025Article
- Identifying a novelWorld journal of clinical cases · 2025Article
- Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.EBioMedicine · 2025Article
- Molecular and clinical aspects of histone-related disorders.Human genomics · 2025Review
- Strabismus in Genetic Syndromes: A Review.Clinical & experimental ophthalmology · 2025Review
- Recombinant human growth hormone treatment of Floating-Harbor syndrome: a case report and literature review.BMC pediatrics · 2025Review
- Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders.American journal of human genetics · 2025Article
- Case Report: Co-occurringFrontiers in genetics · 2025Article
- Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.American journal of human genetics · 2024Article
- Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.American journal of human genetics · 2024Article
- Floating-Harbor Syndrome: A Systematic Literature Review and Case Report.Journal of clinical medicine · 2024Article
- Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder.Journal of human genetics · 2024Article
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Authors and funding
88 authors at 20 institutions in 10 countries.
Dmitrijs RotsRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.
Eric Chater-DiehlGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Alexander J M DingemansRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.
Sarah J GoodmanGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Michelle T SiuGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Cheryl CytrynbaumGenetics 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.
Sanaa ChoufaniGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Ny HoangGenetics 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.
Susan WalkerGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Zain AwamlehGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Joshua CharkowGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Stephen MeynGenetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Rolph PfundtRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Tuula RinneRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Thatjana GardeitchikRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Bert B A de VriesRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.
A Chantal DedenRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Erika LeendersRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Michael KwintRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Constance T R M StumpelDepartment of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 HX Maastricht, the Netherlands.
Servi J C StevensMaastricht University Medical Center, 6229 HX Maastricht, the Netherlands.
Jeroen R VermeulenMaastricht University Medical Center, 6229 HX Maastricht, the Netherlands.
Jeske V T van HarsselDepartment of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.
Danielle G M BoschDepartment of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.
Koen L I van GassenDepartment of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.
Ellen van BinsbergenDepartment of Genetics, University Medical Center 3584 CX Utrecht, Utrecht, the Netherlands.
Christa M de GeusUniversity of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
Hein BrackelCatharina Hospital, 5623 EJ Eindhoven, the Netherlands.
Maja HempelInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Jonas DeneckeDepartment of Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Anne SlavotinekDivision of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94143, USA.
Jonathan StroberDivision of Child Neurology, Department of Neurology & Pediatrics, UCSF, San Francisco, CA 94143, USA.
Amy CrunkGeneDx, Gaithersburg, MD 20877, USA.
Leandra FolkGeneDx, Gaithersburg, MD 20877, USA.
Ingrid M WentzensenGeneDx, Gaithersburg, MD 20877, USA.
Hui YangGeneDx, Gaithersburg, MD 20877, USA.
Fanggeng ZouGeneDx, Gaithersburg, MD 20877, USA.
Francisca MillanGeneDx, Gaithersburg, MD 20877, USA.
Richard PersonGeneDx, Gaithersburg, MD 20877, USA.
Yili XieGeneDx, Gaithersburg, MD 20877, USA.
Shuxi LiuGeneDx, Gaithersburg, MD 20877, USA.
Lilian B OusagerDepartment of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark.
Martin LarsenDepartment of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, Clinical Genetics, University of Southern Denmark, 5230 Odense, Denmark.
Laura Schultz-RogersDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.
Eva MoravaDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.
Eric W KleeDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Ian R BerryYorkshire and North East Genomic Laboratory Hub Central Laboratory, Leeds LS1 3EX, UK.
Jennifer CampbellDepartment of Clinical Genetics, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
Kristin LindstromPhoenix Children's Hospital, Phoenix, AZ 85016 USA.
Brianna PruniskiPhoenix Children's Hospital, Phoenix, AZ 85016 USA.
Ann M NeumeyerMassachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
Jessica A RadleyBirmingham 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.
Chanika PhornphutkulWarren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Berkley SchmidtUniversity of Virginia School of Medicine, Charlottesville, VA 22903, USA.
William G WilsonUniversity of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Katrin ÕunapDepartment 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.
Karit ReinsonDepartment 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.
Sander PajusaluDepartment 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.
Arie van HaeringenDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Claudia RuivenkampDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Roos CuperusDepartment of Paediatrics, Juliana Children's Hospital HAGA, 2545 AA the Hague, the Netherlands.
Fernando Santos-SimarroInstituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.
María Palomares-BraloInstituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.
Marta Pacio-MíguezInstituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain.
Alyssa RitterDivision of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
Elizabeth BhojDivision of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
Elin TønneDepartment of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway.
Kristian TvetenDepartment of Medical genetics, Telemark Hospital Trust, 3710 Skien, Norway.
Gerarda CappuccioDepartment of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy.
Nicola Brunetti-PierriDepartment of Translational Medicine, University of Naples "Federico II," 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 20129 Pozzuoli, Italy.
Leah RoweUniversity of Colorado School of Medicine, Aurora, CO 13001, USA.
Jason BunnUniversity of Colorado School of Medicine, Aurora, CO 13001, USA.
Margarita SaenzUniversity of Colorado School of Medicine, Aurora, CO 13001, USA.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Mareike MertensInstitute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Oana CaluseriuDepartment of Medical Genetics in the Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Małgorzata J M NowaczykDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
Ronald D CohnGenetics 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.
Peter KannuDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Ebba AlkhunaiziGenetics Program, North York General Hospital, Toronto, ON M2K 1E1, Canada.
David ChitayatDivision 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.
Stephen W SchererGenetics 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.
Han G BrunnerRadboud 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.
Lisenka E L M VissersRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.
Tjitske KleefstraRadboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GL Nijmegen, the Netherlands.
David A KoolenRadboud 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.
Rosanna WeksbergGenetics 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.
Hospital for Sick Children · CARadboud University Medical Center · NLRadboud University Nijmegen · NLMaastricht University · NLUniversity Medical Center Utrecht · NLUniversity of Toronto · CAHospital Universitario La Paz · ESUniversity Medical Center Hamburg-Eppendorf · DEUniversity of Colorado Denver · USChildren's Hospital of Philadelphia · USLeiden University Medical Center · NLLeipzig University · DEMayo Clinic in Florida · USOdense University Hospital · DKPhoenix Children's Hospital · USUniversity of Alberta · CAUniversity of Tartu · EEUniversity of Virginia · USBirmingham Women’s and Children’s NHS Foundation Trust · GBBrown University · US
Funding
CIHR IGH-155182CIHR MOP-126054
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.
Indexed as
DNA MethylationEpigenesis, GeneticMutationPhenotypeAbnormalities, MultipleAdenosine TriphosphatasesCase-Control StudiesCohort StudiesCraniofacial AbnormalitiesFemaleGenetic Predisposition to DiseaseGrowth DisordersHeart Septal Defects, VentricularHumansInfant, NewbornMaleAdenosine TriphosphatasesSRCAP protein, humanDNA methylation signatureepigenomicsFloating-Harbor syndromegenotype-phenotype correlationintellectual disabilityneurodevelopmental disordersnon-FLHS SRCAP-related NDDnonsense-mediated decayspeech delaySRCAP
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