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

• DOI: 10.1016/j.ajhg.2021.04.008
• Publication Date: 2021-04-27T16:38:01Z
• Authors: Dmitrijs Rots; Eric Chater-Diehl; Alexander J.M. Di...; 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. ...; Servi J.C. Stevens; Jeroen R. Vermeulen; Jeske V.T. van Ha...; 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-S...; María Palomares-B...; Marta Pacio-Míguez; Alyssa Ritter; Elizabeth Bhoj; Elin Tønne; Kristian Tveten; Gerarda Cappuccio; Nicola Brunetti-P...; Leah Rowe; Jason Bunn; Margarita Saenz; Konrad Platzer; Mareike Mertens; Oana Caluseriu; Małgorzata J.M. N...; Ronald D. Cohn; Peter Kannu; Ebba Alkhunaizi; David Chitayat; Stephen W. Scherer; Han G. Brunner; Lisenka E.L.M. Vi...; Tjitske Kleefstra; David A. Koolen; Rosanna Weksberg
• Keywords: DNA methylation signature; nonsense-mediated decay; Heart Septal Defects, Ventricular; Male; 0301 basic medicine; speech delay; PROTEIN; PHENOTYPE; Medical and Health Sciences; Epigenesis, Genetic; Cohort Studies; Craniofacial Abnormalities; 2.1 Biological and endogenous factors; Paediatrics - Radboud University Medical Center; Aetiology; Growth Disorders; non-FLHS SRCAP-related NDD; Genetics & Heredity; Adenosine Triphosphatases; neurodevelopmental disorders; SOTOS-LIKE; Biological Sciences; SRCAP; AT-HOOK; 3. Good health; Mental Health; Phenotype; intellectual disability; Female; Abnormalities; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences; Multiple; EXON 34; Intellectual and Developmental Disabilities (IDD); 610; genotype-phenotype correlation; DIAGNOSIS; Article; 03 medical and health sciences; Genetic; Clinical Research; Genetics; Humans; Abnormalities, Multiple; Genetic Predisposition to Disease; Floating-Harbor syndrome; SPECTRUM; 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; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; MUTATIONS; Heart Septal Defects; Ventricular; Infant, Newborn; Infant; DNA Methylation; Newborn; GENE; Brain Disorders; Neurodevelopmental Disorders; Case-Control Studies; epigenomics; Mutation; Human Genetics - Radboud University Medical Center; EPISIGNATURES; Epigenesis

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, facial dysmorphism. Here, we present a cohort individuals with clinical features distinct from FLHS truncating (mostly de novo) SRCAP either proximal (n = 28) or distal 5) to locus. Detailed characterization identified shared characteristics: developmental delay without intellectual disability, behavioral psychiatric problems, non-specific features, musculoskeletal issues, hypotonia. Because is known be associated unique set DNA methylation (DNAm) changes blood, DNAm signature, investigated whether there was signature our affected individuals. A machine-learning model, based on negatively classified all tested subjects. Comparing typically developing controls, signature. Based data, refer condition as "non-FLHS SRCAP-related NDD." All five using model while two positively model. This suggests divergent pathogenicity these variants, though clinically group presented NDD, similar group. In summary, for SRCAP, clear relationship between variant location, profile, phenotype. These results highlight power combined epigenetic, molecular, studies identify characterize genotype-epigenotype-phenotype correlations.