Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction

I. Parenti, C. Gervasini, J. Pozojevic, K. S. Wendt, E. Watrin, J. Azzollini, D. Braunholz, K. Buiting, A. Cereda, H. Engels, L. Garavelli, R. Glazar, B. Graffmann, L. Larizza, H. J. Lüdecke, M. Mariani, M. Masciadri, J. Pié, F. J. Ramos, S. RussoA. Selicorni, M. Stefanova, T. M. Strom, R. Werner, J. Wierzba, G. Zampino, G. Gillessen-Kaesbach, D. Wieczorek, F. J. Kaiser

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 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.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

De Lange Syndrome
Molecular Pathology
Counseling
Phenotype
X Chromosome Inactivation
Genetic Counseling
Siblings
Molecular Biology
Mothers
Technology
Mutation
Genes

Keywords

  • Cohesin
  • Cornelia de Lange syndrome
  • HDAC8
  • Mosaicism
  • X-inactivation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Parenti, I., Gervasini, C., Pozojevic, J., Wendt, K. S., Watrin, E., Azzollini, J., ... Kaiser, F. J. (Accepted/In press). Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction. Clinical Genetics. https://doi.org/10.1111/cge.12717

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction. / Parenti, I.; Gervasini, C.; Pozojevic, J.; Wendt, K. S.; Watrin, E.; Azzollini, J.; Braunholz, D.; Buiting, K.; Cereda, A.; Engels, H.; Garavelli, L.; Glazar, R.; Graffmann, B.; Larizza, L.; Lüdecke, H. J.; Mariani, M.; Masciadri, M.; Pié, J.; Ramos, F. J.; Russo, S.; Selicorni, A.; Stefanova, M.; Strom, T. M.; Werner, R.; Wierzba, J.; Zampino, G.; Gillessen-Kaesbach, G.; Wieczorek, D.; Kaiser, F. J.

In: Clinical Genetics, 2016.

Research output: Contribution to journalArticle

Parenti, I, Gervasini, C, Pozojevic, J, Wendt, KS, Watrin, E, Azzollini, J, Braunholz, D, Buiting, K, Cereda, A, Engels, H, Garavelli, L, Glazar, R, Graffmann, B, Larizza, L, Lüdecke, HJ, Mariani, M, Masciadri, M, Pié, J, Ramos, FJ, Russo, S, Selicorni, A, Stefanova, M, Strom, TM, Werner, R, Wierzba, J, Zampino, G, Gillessen-Kaesbach, G, Wieczorek, D & Kaiser, FJ 2016, 'Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction', Clinical Genetics. https://doi.org/10.1111/cge.12717
Parenti, I. ; Gervasini, C. ; Pozojevic, J. ; Wendt, K. S. ; Watrin, E. ; Azzollini, J. ; Braunholz, D. ; Buiting, K. ; Cereda, A. ; Engels, H. ; Garavelli, L. ; Glazar, R. ; Graffmann, B. ; Larizza, L. ; Lüdecke, H. J. ; Mariani, M. ; Masciadri, M. ; Pié, J. ; Ramos, F. J. ; Russo, S. ; Selicorni, A. ; Stefanova, M. ; Strom, T. M. ; Werner, R. ; Wierzba, J. ; Zampino, G. ; Gillessen-Kaesbach, G. ; Wieczorek, D. ; Kaiser, F. J. / Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction. In: Clinical Genetics. 2016.
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T1 - Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction

AU - Parenti, I.

AU - Gervasini, C.

AU - Pozojevic, J.

AU - Wendt, K. S.

AU - Watrin, E.

AU - Azzollini, J.

AU - Braunholz, D.

AU - Buiting, K.

AU - Cereda, A.

AU - Engels, H.

AU - Garavelli, L.

AU - Glazar, R.

AU - Graffmann, B.

AU - Larizza, L.

AU - Lüdecke, H. J.

AU - Mariani, M.

AU - Masciadri, M.

AU - Pié, J.

AU - Ramos, F. J.

AU - Russo, S.

AU - Selicorni, A.

AU - Stefanova, M.

AU - Strom, T. M.

AU - Werner, R.

AU - Wierzba, J.

AU - Zampino, G.

AU - Gillessen-Kaesbach, G.

AU - Wieczorek, D.

AU - Kaiser, F. J.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Cohesin

KW - Cornelia de Lange syndrome

KW - HDAC8

KW - Mosaicism

KW - X-inactivation

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