Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family
Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale...
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MDPI AG
2023-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/6/1275 |
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| author | Paola Concolino Elisa De Paolis Simona Moffa Maria Elisabetta Onori Laura Soldovieri Claudio Ricciardi Tenore Maria De Bonis Claudio Rabacchi Concetta Santonocito Martina Rinelli Sebastiano Calandra Andrea Giaccari Andrea Urbani Angelo Minucci |
| author_facet | Paola Concolino Elisa De Paolis Simona Moffa Maria Elisabetta Onori Laura Soldovieri Claudio Ricciardi Tenore Maria De Bonis Claudio Rabacchi Concetta Santonocito Martina Rinelli Sebastiano Calandra Andrea Giaccari Andrea Urbani Angelo Minucci |
| author_sort | Paola Concolino |
| collection | DOAJ |
| description | Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4–18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases. |
| first_indexed | 2024-03-11T02:25:58Z |
| format | Article |
| id | doaj.art-fe2e26aeb0bf450789c81ff6393012ce |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T02:25:58Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-fe2e26aeb0bf450789c81ff6393012ce2023-11-18T10:35:13ZengMDPI AGGenes2073-44252023-06-01146127510.3390/genes14061275Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian FamilyPaola Concolino0Elisa De Paolis1Simona Moffa2Maria Elisabetta Onori3Laura Soldovieri4Claudio Ricciardi Tenore5Maria De Bonis6Claudio Rabacchi7Concetta Santonocito8Martina Rinelli9Sebastiano Calandra10Andrea Giaccari11Andrea Urbani12Angelo Minucci13Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyCenter for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyCenter for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartment of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartment of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, ItalyCenter for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyNext-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4–18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases.https://www.mdpi.com/2073-4425/14/6/1275familial hypercholesterolemiacopy number variations (CNVs)next-generation sequencing<i>LDLR</i> geneLDL cholesterolAlu sequences |
| spellingShingle | Paola Concolino Elisa De Paolis Simona Moffa Maria Elisabetta Onori Laura Soldovieri Claudio Ricciardi Tenore Maria De Bonis Claudio Rabacchi Concetta Santonocito Martina Rinelli Sebastiano Calandra Andrea Giaccari Andrea Urbani Angelo Minucci Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family Genes familial hypercholesterolemia copy number variations (CNVs) next-generation sequencing <i>LDLR</i> gene LDL cholesterol Alu sequences |
| title | Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family |
| title_full | Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family |
| title_fullStr | Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family |
| title_full_unstemmed | Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family |
| title_short | Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family |
| title_sort | identification and molecular characterization of a novel large scale variant exons 4 18 loss in the ldlr gene as a cause of familial hypercholesterolaemia in an italian family |
| topic | familial hypercholesterolemia copy number variations (CNVs) next-generation sequencing <i>LDLR</i> gene LDL cholesterol Alu sequences |
| url | https://www.mdpi.com/2073-4425/14/6/1275 |
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