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Expanding the clinical spectrum of the "HDAC8-phenotype" - Implications for molecular diagnostics, counselling and risk prediction

Ilaria Parenti 1 Cristina Gervasini 1 Jelena Pozojevic 2 Kerstin S. Wendt Erwan Watrin 3 Jacopo Azzollini 1 Diana Braunholz 2 Karin Buiting Anna Cereda 4 Hartmut Engels Livia Garavelli 5 Renata Glazar Barbara Graffmann Lidia Larizza 1 Hermann-Josef Lüdecke 6 Milena Mariani 4 Maura Masciadri Juan Pié Feliciano J. Ramos Silvia Russo 7 Angelo Selicorni 4 Margarita Stefanova Tim M. Strom Ralf Werner 2 Jolanta Wierzba Giuseppe Zampino 8 Gabriele Gillessen-Kaesbach 2 Dagmar Wieczorek 6 Frank J Kaiser 2
1 Università degli studi di Milano [Milano]
2 Institut für Humangenetik Lübeck
3 IGDR - Institut de Génétique et Développement de Rennes
4 Paediatric Clinical Genetics, MBBM AO S. Gerardo Monza Foundation, University of Milano Bicocca
5 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
6 Institute of Human Genetics - Institut für Humangenetik [Essen]
7 IRCCS Istituto Auxologico Italiano
8 Clinica Pediatrica
Abstract : Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of eleven patients carrying ten distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counselling and risk prediction
Keywords : Cohesin mosaicism HDAC8 Cornelia de Lange syndrome X-inactivation
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01255865
Contributor : Laurent Jonchère <>
Submitted on : Thursday, January 14, 2016 - 9:58:57 AM
Last modification on : Monday, May 4, 2020 - 6:44:01 PM

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UNIV-RENNES1 | CNRS | IGDR | BIOSIT | UR1-UFR-SVE | UNIV-RENNES

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Ilaria Parenti, Cristina Gervasini, Jelena Pozojevic, Kerstin S. Wendt, Erwan Watrin, et al.. Expanding the clinical spectrum of the "HDAC8-phenotype" - Implications for molecular diagnostics, counselling and risk prediction. Clinical Genetics, Wiley, 2016, 89 (5), pp.564-573. ⟨10.1111/cge.12717⟩. ⟨hal-01255865⟩

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