A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome
Por:
Lucia-Campos, C, Valenzuela, I, Latorre-Pellicer, A, Ros-Pardo, D, Gil-Salvador, M, Arnedo, M, Puisac, B, Castells, N, Plaja, A, Tenes, A, Cusco, I, Trujillano, L, Ramos, FJ, Tizzano, EF, Gomez-Puertas, P, Pie, J
Publicada:
1 ago 2022
Resumen:
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 similar to 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.
Filiaciones:
Lucia-Campos, C:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Valenzuela, I:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Latorre-Pellicer, A:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Ros-Pardo, D:
CSIC UAM, Centro Biol Mol Severo Ochoa CBMSO, Mol Modeling Grp, E-28049 Madrid, Spain
Gil-Salvador, M:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Arnedo, M:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Puisac, B:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Castells, N:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Plaja, A:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Tenes, A:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Cusco, I:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Hosp Sant Pau, Dept Genet, E-08041 Barcelona, Spain
Trujillano, L:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Ramos, FJ:
Hosp Clin Universitario Lozano Blesa, Univers Zaragoza, Sch Med, CIBERERGCV02 & IISAragon,Serv Paediat,Unit Clin G, E-50009 Zaragoza, Spain
Tizzano, EF:
Mol Genet Hosp Vall Hebron, Dept Clin, E-50009 Barcelona, Spain
Vall Hebron Res Inst, Med Genet Grp, E-08035 Barcelona, Spain
Gomez-Puertas, P:
CSIC UAM, Centro Biol Mol Severo Ochoa CBMSO, Mol Modeling Grp, E-28049 Madrid, Spain
Pie, J:
Univers Zaragoza, Sch Med, Unit Clin Genet & Funct Gen, CIBERER GCV02 & IISAragon,Dept Pharmacol Physiol, Aragon, Spain
Green Published, gold, Gold, Green
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