Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay
Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a d...
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| Veröffentlicht in: | Clinical genetics 2024-09, Vol.106 (3), p.354-359 |
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| creator | Zhou, Wei Wang, Chunli Fu, Luhan Shi, Wei Zhang, Aihua Jia, Zhanjun Zhao, Xiaoke Fu, Dalin Zheng, Bixia |
| description | Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX‐related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High‐throughput chromosome conformation capture (Hi‐C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7‐related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi‐C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.
We present two patients with a 4q31 deletion that affects the regulatory region of FBXW7, potentially by disrupting the composition of TADs. This study highlights the importance of considering CNVs and their impact on the composition and function of TADs in elucidating the underlying molecular mechanisms of neurodevelopmental disorders. |
| doi_str_mv | 10.1111/cge.14548 |
| format | Article |
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We present two patients with a 4q31 deletion that affects the regulatory region of FBXW7, potentially by disrupting the composition of TADs. This study highlights the importance of considering CNVs and their impact on the composition and function of TADs in elucidating the underlying molecular mechanisms of neurodevelopmental disorders.</description><identifier>ISSN: 0009-9163</identifier><identifier>ISSN: 1399-0004</identifier><identifier>EISSN: 1399-0004</identifier><identifier>DOI: 10.1111/cge.14548</identifier><identifier>PMID: 38780184</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Cdc4 protein ; Child ; Child, Preschool ; Chromatin ; Chromosome 4 ; Chromosome deletion ; Chromosomes, Human, Pair 4 - genetics ; Copy number ; Developmental Disabilities - genetics ; Developmental Disabilities - pathology ; DNA Copy Number Variations - genetics ; F-Box-WD Repeat-Containing Protein 7 - genetics ; FBXW7 ; Female ; Gene duplication ; Genetic Predisposition to Disease ; Humans ; Infant ; Male ; Neural stem cells ; neurodevelopmental delay ; Neurodevelopmental disorders ; Neurodevelopmental Disorders - genetics ; Progenitor cells ; Regulatory Sequences, Nucleic Acid - genetics ; topologically associated domains</subject><ispartof>Clinical genetics, 2024-09, Vol.106 (3), p.354-359</ispartof><rights>2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3138-a6feddfadcd5895015bbdb6a49f96d5cfcd41e1657d0089163b116bde9134f093</cites><orcidid>0000-0001-7438-4404</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcge.14548$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcge.14548$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38780184$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Wei</creatorcontrib><creatorcontrib>Wang, Chunli</creatorcontrib><creatorcontrib>Fu, Luhan</creatorcontrib><creatorcontrib>Shi, Wei</creatorcontrib><creatorcontrib>Zhang, Aihua</creatorcontrib><creatorcontrib>Jia, Zhanjun</creatorcontrib><creatorcontrib>Zhao, Xiaoke</creatorcontrib><creatorcontrib>Fu, Dalin</creatorcontrib><creatorcontrib>Zheng, Bixia</creatorcontrib><title>Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay</title><title>Clinical genetics</title><addtitle>Clin Genet</addtitle><description>Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX‐related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High‐throughput chromosome conformation capture (Hi‐C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7‐related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi‐C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.
We present two patients with a 4q31 deletion that affects the regulatory region of FBXW7, potentially by disrupting the composition of TADs. This study highlights the importance of considering CNVs and their impact on the composition and function of TADs in elucidating the underlying molecular mechanisms of neurodevelopmental disorders.</description><subject>Cdc4 protein</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromatin</subject><subject>Chromosome 4</subject><subject>Chromosome deletion</subject><subject>Chromosomes, Human, Pair 4 - genetics</subject><subject>Copy number</subject><subject>Developmental Disabilities - genetics</subject><subject>Developmental Disabilities - pathology</subject><subject>DNA Copy Number Variations - genetics</subject><subject>F-Box-WD Repeat-Containing Protein 7 - genetics</subject><subject>FBXW7</subject><subject>Female</subject><subject>Gene duplication</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Infant</subject><subject>Male</subject><subject>Neural stem cells</subject><subject>neurodevelopmental delay</subject><subject>Neurodevelopmental disorders</subject><subject>Neurodevelopmental Disorders - genetics</subject><subject>Progenitor cells</subject><subject>Regulatory Sequences, Nucleic Acid - genetics</subject><subject>topologically associated domains</subject><issn>0009-9163</issn><issn>1399-0004</issn><issn>1399-0004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFO3DAQhi1EBdttD7xAZYlLe8jiqe1sfGxXQJGQuIDoLXLs8RKUxMF2QHn7eruUA1LnMh7p0yfP_IScAFtBrjOzxRUIKaoDsgCuVMEYE4dkkZsqFJT8mHyM8TGPfC3VETnm1bpiUIkFGTd-nOkw9Q0G-qxDq4cUqU5UPHFYcaqdQ5PaYUvTA9KA26nTyYd592z9QL2jFz9_36-pjtGbVie09KVND3TAKXiLz9j5scch6Y5a7PT8iXxwuov4-bUvyd3F-e3mV3F9c3m1-XFdGA68KnTp0FqnrbGyUpKBbBrblFoop0orjTNWAEIp15axardjA1A2FhVw4ZjiS_J17x2Df5owprpvo8Gu0wP6KdacSfVdVjzXkpy-Qx_9FIb8u0wpEJyB2gm_7SkTfIwBXT2GttdhroHVuxjqHEP9N4bMfnk1Tk2P9o38d_cMnO2Bl7bD-f-menN5vlf-AZ70kVM</recordid><startdate>202409</startdate><enddate>202409</enddate><creator>Zhou, Wei</creator><creator>Wang, Chunli</creator><creator>Fu, Luhan</creator><creator>Shi, Wei</creator><creator>Zhang, Aihua</creator><creator>Jia, Zhanjun</creator><creator>Zhao, Xiaoke</creator><creator>Fu, Dalin</creator><creator>Zheng, Bixia</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7438-4404</orcidid></search><sort><creationdate>202409</creationdate><title>Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay</title><author>Zhou, Wei ; Wang, Chunli ; Fu, Luhan ; Shi, Wei ; Zhang, Aihua ; Jia, Zhanjun ; Zhao, Xiaoke ; Fu, Dalin ; Zheng, Bixia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3138-a6feddfadcd5895015bbdb6a49f96d5cfcd41e1657d0089163b116bde9134f093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Cdc4 protein</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromatin</topic><topic>Chromosome 4</topic><topic>Chromosome deletion</topic><topic>Chromosomes, Human, Pair 4 - genetics</topic><topic>Copy number</topic><topic>Developmental Disabilities - genetics</topic><topic>Developmental Disabilities - pathology</topic><topic>DNA Copy Number Variations - genetics</topic><topic>F-Box-WD Repeat-Containing Protein 7 - genetics</topic><topic>FBXW7</topic><topic>Female</topic><topic>Gene duplication</topic><topic>Genetic Predisposition to Disease</topic><topic>Humans</topic><topic>Infant</topic><topic>Male</topic><topic>Neural stem cells</topic><topic>neurodevelopmental delay</topic><topic>Neurodevelopmental disorders</topic><topic>Neurodevelopmental Disorders - genetics</topic><topic>Progenitor cells</topic><topic>Regulatory Sequences, Nucleic Acid - genetics</topic><topic>topologically associated domains</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhou, Wei</creatorcontrib><creatorcontrib>Wang, Chunli</creatorcontrib><creatorcontrib>Fu, Luhan</creatorcontrib><creatorcontrib>Shi, Wei</creatorcontrib><creatorcontrib>Zhang, Aihua</creatorcontrib><creatorcontrib>Jia, Zhanjun</creatorcontrib><creatorcontrib>Zhao, Xiaoke</creatorcontrib><creatorcontrib>Fu, Dalin</creatorcontrib><creatorcontrib>Zheng, Bixia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Wei</au><au>Wang, Chunli</au><au>Fu, Luhan</au><au>Shi, Wei</au><au>Zhang, Aihua</au><au>Jia, Zhanjun</au><au>Zhao, Xiaoke</au><au>Fu, Dalin</au><au>Zheng, Bixia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay</atitle><jtitle>Clinical genetics</jtitle><addtitle>Clin Genet</addtitle><date>2024-09</date><risdate>2024</risdate><volume>106</volume><issue>3</issue><spage>354</spage><epage>359</epage><pages>354-359</pages><issn>0009-9163</issn><issn>1399-0004</issn><eissn>1399-0004</eissn><abstract>Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX‐related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High‐throughput chromosome conformation capture (Hi‐C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7‐related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi‐C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.
We present two patients with a 4q31 deletion that affects the regulatory region of FBXW7, potentially by disrupting the composition of TADs. This study highlights the importance of considering CNVs and their impact on the composition and function of TADs in elucidating the underlying molecular mechanisms of neurodevelopmental disorders.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>38780184</pmid><doi>10.1111/cge.14548</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-7438-4404</orcidid></addata></record> |
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| subjects | Cdc4 protein Child Child, Preschool Chromatin Chromosome 4 Chromosome deletion Chromosomes, Human, Pair 4 - genetics Copy number Developmental Disabilities - genetics Developmental Disabilities - pathology DNA Copy Number Variations - genetics F-Box-WD Repeat-Containing Protein 7 - genetics FBXW7 Female Gene duplication Genetic Predisposition to Disease Humans Infant Male Neural stem cells neurodevelopmental delay Neurodevelopmental disorders Neurodevelopmental Disorders - genetics Progenitor cells Regulatory Sequences, Nucleic Acid - genetics topologically associated domains |
| title | Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay |
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