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Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction
University of Lubeck, Germany; University of Milan, Italy.
University of Milan, Italy.
University of Lubeck, Germany.
Erasmus MC, Netherlands.
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2016 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 89, no 5, 564-573 p.Article in journal (Refereed) PublishedText
Abstract [en]

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 11 patients carrying 10 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 counseling and risk prediction.

Place, publisher, year, edition, pages
WILEY-BLACKWELL , 2016. Vol. 89, no 5, 564-573 p.
Keyword [en]
cohesin; Cornelia de Lange syndrome; HDAC8; mosaicism; X-inactivation
National Category
Medical Genetics Psychiatry
URN: urn:nbn:se:liu:diva-128733DOI: 10.1111/cge.12717ISI: 000374974600007PubMedID: 26671848OAI: diva2:932320

Funding Agencies|German Federal Ministry of Education and Research (BMBF); the Netherlands Organization for Health Research and Development (ZonMW); Agence Nationale de la Recherche (ANR); Schwerpunktprogramm (SPP) fur medizinische Genetik of the University of Lubeck; Spains Ministry of Health-ISCIII [FIS PI12-01318]; Gobierno de Aragon [B20]; Accordo Quadro Universita-Regione Lombardia: SAL31 [17292]

Available from: 2016-06-01 Created: 2016-05-30 Last updated: 2016-06-15

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Graffmann, B.Stefanova, Margarita
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Department of Paediatrics in LinköpingDivision of Cell BiologyFaculty of Medicine and Health SciencesDepartment of Clinical Pathology and Clinical Genetics
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