Copy number variations residing outside the SHOX enhancer region are involved in Short Stature and Léri-Weill dyschondrosteosis
Autor: | Deepak Babu, Antonella Fanelli, Alessia Cucci, Antonia Follenzi, Alice Monzani, Wael Al Essa, Mara Giordano, Flavia Prodam, Simonetta Bellone, Andrea Secco, Simona Mellone, Silvia Vannelli |
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Rok vydání: | 2021 |
Předmět: |
Diagnostic methods
DNA Copy Number Variations Dwarfism Haploinsufficiency QH426-470 Biology Osteochondrodysplasias Short stature Short Stature Homeobox Protein LWD Genetics medicine Humans array CGH Copy-number variation Enhancer Molecular Biology Léri–Weill dyschondrosteosis Genetics (clinical) Growth Disorders Breakpoint Original Articles medicine.disease Phenotype short stature Normal stature Original Article enhancers medicine.symptom SHOX |
Zdroj: | Molecular Genetics & Genomic Medicine Molecular Genetics & Genomic Medicine, Vol 10, Iss 1, Pp n/a-n/a (2022) |
ISSN: | 2324-9269 |
Popis: | Background SHOX enhancer CNVs, affecting one or more of the seven recognized evolutionary conserved non‐coding elements (CNEs) represent one of the most frequent cause of SHOX‐haploinsufficiency. During the diagnostic workflow deletions/duplications have been identified downstream SHOX not including any of the these CNEs. Methods Fine tiling aCGH and breakpoint PCR were used to characterize the critical interval and to search for novel alterations in a cohort of selected patients. Results Screening of 252 controls provided evidence that duplications in this area represent likely benign variants whereas none of the deletions were detected. These findings suggested that other alterations relevant for SHOX‐haploinsufficiency might be missed by the standard diagnostic methods. To identify such undisclosed elements, the aCGH was used to reanalyze 52 unresolved cases with clinical features strongly suggestive of SHOX‐haploinsufficiency. This analysis followed by the screening of 210 patients detected two partially overlapping small deletions of ~12 and ~8 kb in four unrelated individuals, approximately 15 kb downstream SHOX, that were absent in 720 normal stature individuals. Conclusion Our results strengthen the hypothesis that alterations of yet unidentified cis‐regulatory elements residing outside those investigated through conventional methods, might explain the phenotype in ISS/LWD patients thus enlarging the spectrum of variants contributing to SHOX‐haploinsufficiency. The characterization of deletions identified in Short Staure patients through fine tiling aCGH narrowed down a critical interval downstream the enhancer that might contains elements relevant for SHOX expression. To identify undisclosed |
Databáze: | OpenAIRE |
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