Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders
IntroductionBalanced chromosomal abnormalities (BCAs) are structural variations that can underlie a wide spectrum of neurodevelopmental disorders, often remaining undetected by conventional diagnostic approaches. Whole-genome sequencing (WGS) allows for base-pair resolution of structural variants ac...
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Frontiers Media S.A.
2025-07-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1603513/full |
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| author | Simona Mellone Alice Spano Denise Vurchio Giulia Borgonovi Giulia Borgonovi Alessandro Ugonotti Giulia Paglino Alba Bianco Sara Ronzani Maurizio Sciancalepore Flavia Prodam Flavia Prodam Amanda Papa Maurizio Viri Umberto Dianzani Umberto Dianzani Mara Giordano Mara Giordano |
| author_facet | Simona Mellone Alice Spano Denise Vurchio Giulia Borgonovi Giulia Borgonovi Alessandro Ugonotti Giulia Paglino Alba Bianco Sara Ronzani Maurizio Sciancalepore Flavia Prodam Flavia Prodam Amanda Papa Maurizio Viri Umberto Dianzani Umberto Dianzani Mara Giordano Mara Giordano |
| author_sort | Simona Mellone |
| collection | DOAJ |
| description | IntroductionBalanced chromosomal abnormalities (BCAs) are structural variations that can underlie a wide spectrum of neurodevelopmental disorders, often remaining undetected by conventional diagnostic approaches. Whole-genome sequencing (WGS) allows for base-pair resolution of structural variants across the entire genome, making it a powerful tool to detect cryptic chromosomal rearrangements and refine breakpoint mapping. RNA sequencing (RNA-Seq), by enabling the detection of gene expression changes and fusion transcripts, provides complementary functional insights into the consequences of genomic alterations. This study integrated WGS and RNA-Seq to precisely characterize the breakpoints and assess the functional impact of de novo BCAs in two unsolved cases of Neurodevelopmental Disorders.Materials and methodsShort read WGS was used to identify the chromosomal breakpoints and gene disruptions caused by BCAs. RNA-Seq on blood RNA was employed to detect differential gene expression and potential fusion transcripts of disrupted genes.ResultsIn the first case, the inversion inv(8) (p11.2q13) disrupted two genes at the breakpoints, namely, CHD7 and SLC20A2. These genes are in opposite orientations, and the inversion realigned them in the same direction, generating two novel fusion genes. Disruption of CHD7 confirmed the suspected diagnosis of CHARGE syndrome. The interruption of SLC20A2, commonly associated with neurological symptoms, prompted further clinical evaluation. RNA-Seq identified in-frame fusion transcripts from the chimeric genes in the blood, suggesting a potential deleterious phenotypic effect. In the second case, WGS revealed a balanced translocation t(17; 22) (q25; q13) that disrupted EP300 at 22q25, confirming Rubinstein-Taybi syndrome. The concurrent disruption of RBFOX3 at 17q13 suggested additional neurological implications, particularly related to epilepsy. Transcriptomic analysis demonstrated the monoallelic and significantly reduced expression of EP300.ConclusionThese findings highlight the crucial role of WGS in identifying disease-associated BCAs and underscore the complementary value of RNA-Seq in assessing their functional consequences. This integrated approach enhanced diagnostic accuracy and clinical management, paving the way for more comprehensive and personalized care in these two patients. |
| format | Article |
| id | doaj-art-db40cb6aec9b43aa8a69b58e71992a55 |
| institution | Matheson Library |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-db40cb6aec9b43aa8a69b58e71992a552025-07-07T07:44:34ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-07-011610.3389/fgene.2025.16035131603513Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disordersSimona Mellone0Alice Spano1Denise Vurchio2Giulia Borgonovi3Giulia Borgonovi4Alessandro Ugonotti5Giulia Paglino6Alba Bianco7Sara Ronzani8Maurizio Sciancalepore9Flavia Prodam10Flavia Prodam11Amanda Papa12Maurizio Viri13Umberto Dianzani14Umberto Dianzani15Mara Giordano16Mara Giordano17Unit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDivision of Endocrinology, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Child Neuropsychiatry, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Child Neuropsychiatry, University Hospital “Maggiore della Carità”, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyUnit of Genetics, Clinical Biochemistry, University Hospital “Maggiore della Carità”, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyIntroductionBalanced chromosomal abnormalities (BCAs) are structural variations that can underlie a wide spectrum of neurodevelopmental disorders, often remaining undetected by conventional diagnostic approaches. Whole-genome sequencing (WGS) allows for base-pair resolution of structural variants across the entire genome, making it a powerful tool to detect cryptic chromosomal rearrangements and refine breakpoint mapping. RNA sequencing (RNA-Seq), by enabling the detection of gene expression changes and fusion transcripts, provides complementary functional insights into the consequences of genomic alterations. This study integrated WGS and RNA-Seq to precisely characterize the breakpoints and assess the functional impact of de novo BCAs in two unsolved cases of Neurodevelopmental Disorders.Materials and methodsShort read WGS was used to identify the chromosomal breakpoints and gene disruptions caused by BCAs. RNA-Seq on blood RNA was employed to detect differential gene expression and potential fusion transcripts of disrupted genes.ResultsIn the first case, the inversion inv(8) (p11.2q13) disrupted two genes at the breakpoints, namely, CHD7 and SLC20A2. These genes are in opposite orientations, and the inversion realigned them in the same direction, generating two novel fusion genes. Disruption of CHD7 confirmed the suspected diagnosis of CHARGE syndrome. The interruption of SLC20A2, commonly associated with neurological symptoms, prompted further clinical evaluation. RNA-Seq identified in-frame fusion transcripts from the chimeric genes in the blood, suggesting a potential deleterious phenotypic effect. In the second case, WGS revealed a balanced translocation t(17; 22) (q25; q13) that disrupted EP300 at 22q25, confirming Rubinstein-Taybi syndrome. The concurrent disruption of RBFOX3 at 17q13 suggested additional neurological implications, particularly related to epilepsy. Transcriptomic analysis demonstrated the monoallelic and significantly reduced expression of EP300.ConclusionThese findings highlight the crucial role of WGS in identifying disease-associated BCAs and underscore the complementary value of RNA-Seq in assessing their functional consequences. This integrated approach enhanced diagnostic accuracy and clinical management, paving the way for more comprehensive and personalized care in these two patients.https://www.frontiersin.org/articles/10.3389/fgene.2025.1603513/fullneurodevelopmental disordersbalanced chromosomal abnormalitiesCHD7SLC20A2EP300RBFOX3 |
| spellingShingle | Simona Mellone Alice Spano Denise Vurchio Giulia Borgonovi Giulia Borgonovi Alessandro Ugonotti Giulia Paglino Alba Bianco Sara Ronzani Maurizio Sciancalepore Flavia Prodam Flavia Prodam Amanda Papa Maurizio Viri Umberto Dianzani Umberto Dianzani Mara Giordano Mara Giordano Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders Frontiers in Genetics neurodevelopmental disorders balanced chromosomal abnormalities CHD7 SLC20A2 EP300 RBFOX3 |
| title | Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| title_full | Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| title_fullStr | Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| title_full_unstemmed | Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| title_short | Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| title_sort | integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders |
| topic | neurodevelopmental disorders balanced chromosomal abnormalities CHD7 SLC20A2 EP300 RBFOX3 |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1603513/full |
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