Maria J Nabais Sá1, Philip J Jensik2, Stacey R McGee2, Michael J Parker3, Nayana Lahiri4, Evan P McNeil5, Hester Y Kroes6, Randi J Hagerman7,8, Rachel E Harrison9, Tara Montgomery10, Miranda Splitt10, Elizabeth E Palmer11,12, Rani K Sachdev11,12, Heather C Mefford13, Abbey A Scott14, Julian A Martinez-Agosto15,16, Rüdiger Lorenz17, Naama Orenstein18,19, Jonathan N Berg20,21, Jeanne Amiel22, Delphine Heron23, Boris Keren23, Jan-Maarten Cobben24,25, Leonie A Menke24, Elysa J Marco26, John M Graham27, Tyler Mark Pierson28, Ehsan Ghayoor Karimiani29, Reza Maroofian29, M Chiara Manzini30, Edmund S Cauley30, Roberto Colombo31,32, Sylvie Odent33, Christele Dubourg34, Chanika Phornphutkul35, Arjan P M de Brouwer1, Bert B A de Vries36, Anneke T Vulto-vanSilfhout1. 1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA. 3. Sheffield Clinical Genetics Service, OPD2 Northern General Hospital, Sheffield, UK. 4. Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust & St George's, University of London, London, UK. 5. Dartmouth Geisel School of Medicine, Hanover, NH, USA. 6. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 7. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis School of Medicine, Sacramento, Sacramento, CA, USA. 8. Department of Pediatrics, University of California Davis Medical Center, Sacramento, Sacramento, CA, USA. 9. Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK. 10. Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 11. Sydney Children's Hospital, Randwick, NSW, Australia. 12. School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Sydney, NSW, Australia. 13. Department of Pediatrics, Division of Genetic Medicine, University of Washington-Seattle, Seattle, WA, USA. 14. Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA. 15. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 16. Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 17. Ludwig-Konrad-Str. 14, Bad Wildungen, Germany. 18. Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. 19. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 20. Department of Clinical Genetics, Ninewells Hospital and Medical School, Dundee, Angus, UK. 21. Clinical Genetics, University of Dundee, Dundee, Angus, UK. 22. Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique, INSERM UMR 1163, Institut Imagine, Paris, France. 23. Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Paris, France. 24. Department of Pediatrics, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 25. North West Thames Genetics NHS, Northwick Park Hospital, London, UK. 26. Department of Child Neurology, Cortica Healthcare, San Rafael, CA, USA. 27. Division of Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 28. Department of Pediatrics, Department of Neurology, and the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 29. Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, UK. 30. GW Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 31. Faculty of Medicine"Agostino Gemelli"Catholic University of the Sacred Heart, Rome, Italy. 32. Center for the Study of Rare Inherited Diseases (CeSMER), Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy. 33. Service de Génétique Clinique, CLAD-Ouest CHU Rennes, Univ Rennes, CNRS 6290 Institut de Génétique et Développement de Rennes (IGDR), Rennes, France. 34. Univ Rennes, CHU Rennes, CNRS, IGDR, UMR 6290, Rennes, France. 35. Division of Human Genetics, Department of Pediatrics, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA. 36. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Bert.deVries@radboudumc.nl.
Abstract
PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.
PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.
Authors: Dong Li; Michael E March; Paola Fortugno; Liza L Cox; Leticia S Matsuoka; Rosanna Monetta; Christoph Seiler; Louise C Pyle; Emma C Bedoukian; María José Sánchez-Soler; Oana Caluseriu; Katheryn Grand; Allison Tam; Alicia R P Aycinena; Letizia Camerota; Yiran Guo; Patrick Sleiman; Bert Callewaert; Candy Kumps; Annelies Dheedene; Michael Buckley; Edwin P Kirk; Anne Turner; Benjamin Kamien; Chirag Patel; Meredith Wilson; Tony Roscioli; John Christodoulou; Timothy C Cox; Elaine H Zackai; Francesco Brancati; Hakon Hakonarson; Elizabeth J Bhoj Journal: Hum Genet Date: 2021-04-03 Impact factor: 5.881