A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

Genes (Basel). 2022 Aug 8;13(8):1413. doi: 10.3390/genes13081413.


Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient's phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.

Keywords: Cornelia de Lange syndrome; HDAC8; array CGH; copy number variants; genetic diagnosis; genetic disorder; intragenic duplication.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • De Lange Syndrome* / genetics
  • De Lange Syndrome* / pathology
  • Exons
  • Heterozygote
  • Histone Deacetylases / genetics
  • Humans
  • Phenotype
  • Repressor Proteins / genetics


  • Cell Cycle Proteins
  • NIPBL protein, human
  • Repressor Proteins
  • HDAC8 protein, human
  • Histone Deacetylases

Grants and funding

This work was supported by the Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) (Ref. PI19/01860, to F.J.R. and J.P.) and Diputación General de Aragón-FEDER: European Social Fund (Grupo de Referencia B32_17R/B32_20R, to J.P.). A.L.-P. is supported by a “Juan de la Cierva-Incorporación” postdoctoral grant from MICIU (Spanish Ministry of Science and Universities), M.G.-S. is supported by a Predoctoral Fellowship from the Diputación General de Aragón, and C.L.-C. is supported by a Predoctoral Fellowship from the MH-ISCIII. This work was also supported by Spanish government grants RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) and DTS20-00024 (ISCIII) to P.G.-P., as well as funds from the European JPIAMR network “EPIC-Alliance” to P.G.-P. The computational support of the “Centro de Computación Científica CCC-UAM” is gratefully recognized. This work was also partially supported by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI20/01767) to A.P. and by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI18/000687 to E.F.T.