HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype
| Autor: | Severi G., Bonora E., Perri A., Scarano E., Mazzanti L., Isidori F., Zuntini R., Menabo S., Graziano C. |
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| Přispěvatelé: | Severi G., Bonora E., Perri A., Scarano E., Mazzanti L., Isidori F., Zuntini R., Menabo S., Graziano C. |
| Rok vydání: | 2018 |
| Předmět: |
Haploinsufficiency
Osteochondrodysplasias Whole Exome Sequencing Histone Deacetylases Brachydactyly-mental retardation syndrome Short Stature Homeobox Protein Growth Disorder Histone Deacetylase De Lange Syndrome Exome Sequencing Humans Osteochondrodysplasia Child Frameshift Mutation Growth Disorders Comparative Genomic Hybridization Repressor Protein Dual molecular diagnosi Pedigree Repressor Proteins Phenotype HDAC8 Female Gene Deletion SHOX Human |
| Zdroj: | Cytogenetic and genome research. 157(3) |
| ISSN: | 1424-859X |
| Popis: | We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis. |
| Databáze: | OpenAIRE |
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