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 StumpelServi 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, 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

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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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume108
Issue number6
Pages (from-to)1053-1068
ISSN0002-9297
DOIs
Publication statusPublished - 3. Jun 2021

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

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