Korbinian M Riedhammer1,2, Anna L Burgemeister3, Vincent Cantagrel4, Jeanne Amiel5, Karine Siquier-Pernet4, Nathalie Boddaert6, Jozef Hertecant7, Patricia L Kannouche8, Caroline Pouvelle8, Stephanie Htun9, Anne M Slavotinek9, Christian Beetz10, Dan Diego-Alvarez10, Kapil Kampe10, Nicole Fleischer11, Zain Awamleh12, Rosanna Weksberg12,13,14, Robert Kopajtich1,15, Thomas Meitinger1, Jehan Suleiman16,17, Ayman W El-Hattab18,19,20. 1. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany. 2. Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany. 3. Genetikum, Genetic Counseling and Diagnostics, 70173 Stuttgart, Germany. 4. Developmental Brain Disorders Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR, 75015 Paris, France. 5. Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Université Paris Cité, Imagine Institute, 75015 Paris, France. 6. Département de radiologie pédiatrique, INSERM UMR 1163 and INSERM U1000, AP-HP, Necker Enfants Malades Hospital, 75015 Paris, France. 7. Division of Genetics and Metabolics, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates. 8. CNRS UMR 9019, Université Paris-Saclay, Equipe labellisée Ligue contre le Cancer, Gustave Roussy, 94805 Villejuif, France. 9. Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143, USA. 10. Centogene GmbH, 18055 Rostock, Germany. 11. FDNA Inc., Boston, MA 02111, USA. 12. Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. 13. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 14. Department of Molecular Genetics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A1, Canada. 15. Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. 16. Division of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates. 17. Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 18. Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates. 19. Pediatrics Department, University Hospital Sharjah, Sharjah, United Arab Emirates. 20. Genetics and Metabolic Department, KidsHeart Medical Center, Abu Dhabi, United Arab Emirates.
Abstract
BACKGROUND: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. METHODS: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.
BACKGROUND: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. METHODS: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.
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