Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3
The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublish...
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| Veröffentlicht in: | American journal of medical genetics. Part A 2021-11, Vol.185 (11), p.3446-3458 |
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| creator | Schirwani, Schaida Albaba, Shadi Carere, Deanna Alexis Guillen Sacoto, Maria J. Milan Zamora, Francisca Si, Yue Rabin, Rachel Pappas, John Renaud, Deborah L. Hauser, Natalie Reid, Evan Blanchet, Patricia Foulds, Nichola Dixit, Abhijit Fisher, Richard Armstrong, Ruth Isidor, Bertrand Cogne, Benjamin Schrier Vergano, Samantha Demirdas, Serwet Dykzeul, Natalie Cohen, Julie S. Grand, Katheryn Morel, Dayna Slavotinek, Anne Albassam, Hessa F. Naik, Swati Dean, John Ragge, Nicola Cinzia, Costa Tedesco, Maria Giovanna Harrison, Rachel E. Bouman, Arjan Palen, Emily Challman, Thomas D. Willemsen, Marjolein H. Vogt, Julie Cunniff, Christopher Bergstrom, Katherine Walia, Jagdeep S. Bruel, Ange‐Line Kini, Usha Alkuraya, Fowzan S. Slegesky, Valerie Meeks, Naomi Girotto, Paula Johnson, Diana Newbury‐Ecob, Ruth Ockeloen, Charlotte W. Prontera, Paolo Lynch, Sally Ann Li, Dong Graham, John M. Balasubramanian, Meena |
| description | The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants. |
| doi_str_mv | 10.1002/ajmg.a.62465 |
| format | Article |
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In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.</description><identifier>ISSN: 1552-4825</identifier><identifier>EISSN: 1552-4833</identifier><identifier>DOI: 10.1002/ajmg.a.62465</identifier><identifier>PMID: 34436830</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Adolescent ; Adult ; ASXL3 ; ASXL3‐related syndrome ; Bainbridge–Ropers syndrome ; BRPS ; Child ; Child, Preschool ; Developmental Disabilities - epidemiology ; Developmental Disabilities - genetics ; Developmental Disabilities - physiopathology ; Female ; Genetic Predisposition to Disease ; Genetic Variation - genetics ; Genotype & phenotype ; Humans ; Hypertelorism - genetics ; Hypertelorism - physiopathology ; intellectual disability ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Male ; Muscle Hypotonia - genetics ; Muscle Hypotonia - physiopathology ; Mutation - genetics ; Neurodevelopmental disorders ; Neurodevelopmental Disorders - epidemiology ; Neurodevelopmental Disorders - genetics ; Neurodevelopmental Disorders - physiopathology ; Phenotype ; Phenotypes ; speech impairment ; Transcription Factors - genetics ; Young Adult</subject><ispartof>American journal of medical genetics. 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Part A</title><addtitle>Am J Med Genet A</addtitle><description>The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.</description><subject>Adolescent</subject><subject>Adult</subject><subject>ASXL3</subject><subject>ASXL3‐related syndrome</subject><subject>Bainbridge–Ropers syndrome</subject><subject>BRPS</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Developmental Disabilities - epidemiology</subject><subject>Developmental Disabilities - genetics</subject><subject>Developmental Disabilities - physiopathology</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Variation - genetics</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Hypertelorism - genetics</subject><subject>Hypertelorism - physiopathology</subject><subject>intellectual disability</subject><subject>Intellectual Disability - genetics</subject><subject>Intellectual Disability - physiopathology</subject><subject>Male</subject><subject>Muscle Hypotonia - genetics</subject><subject>Muscle Hypotonia - physiopathology</subject><subject>Mutation - genetics</subject><subject>Neurodevelopmental disorders</subject><subject>Neurodevelopmental Disorders - epidemiology</subject><subject>Neurodevelopmental Disorders - genetics</subject><subject>Neurodevelopmental Disorders - physiopathology</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>speech impairment</subject><subject>Transcription Factors - genetics</subject><subject>Young 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the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3</title><author>Schirwani, Schaida ; Albaba, Shadi ; Carere, Deanna Alexis ; Guillen Sacoto, Maria J. ; Milan Zamora, Francisca ; Si, Yue ; Rabin, Rachel ; Pappas, John ; Renaud, Deborah L. ; Hauser, Natalie ; Reid, Evan ; Blanchet, Patricia ; Foulds, Nichola ; Dixit, Abhijit ; Fisher, Richard ; Armstrong, Ruth ; Isidor, Bertrand ; Cogne, Benjamin ; Schrier Vergano, Samantha ; Demirdas, Serwet ; Dykzeul, Natalie ; Cohen, Julie S. ; Grand, Katheryn ; Morel, Dayna ; Slavotinek, Anne ; Albassam, Hessa F. ; Naik, Swati ; Dean, John ; Ragge, Nicola ; Cinzia, Costa ; Tedesco, Maria Giovanna ; Harrison, Rachel E. ; Bouman, Arjan ; Palen, Emily ; Challman, Thomas D. ; Willemsen, Marjolein H. ; Vogt, Julie ; Cunniff, Christopher ; Bergstrom, Katherine ; Walia, Jagdeep S. ; Bruel, Ange‐Line ; Kini, Usha ; Alkuraya, Fowzan S. ; Slegesky, Valerie 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Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of medical genetics. Part A</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schirwani, Schaida</au><au>Albaba, Shadi</au><au>Carere, Deanna Alexis</au><au>Guillen Sacoto, Maria J.</au><au>Milan Zamora, Francisca</au><au>Si, Yue</au><au>Rabin, Rachel</au><au>Pappas, John</au><au>Renaud, Deborah L.</au><au>Hauser, Natalie</au><au>Reid, Evan</au><au>Blanchet, Patricia</au><au>Foulds, Nichola</au><au>Dixit, Abhijit</au><au>Fisher, Richard</au><au>Armstrong, Ruth</au><au>Isidor, Bertrand</au><au>Cogne, Benjamin</au><au>Schrier Vergano, Samantha</au><au>Demirdas, Serwet</au><au>Dykzeul, Natalie</au><au>Cohen, Julie S.</au><au>Grand, Katheryn</au><au>Morel, Dayna</au><au>Slavotinek, Anne</au><au>Albassam, Hessa F.</au><au>Naik, Swati</au><au>Dean, John</au><au>Ragge, Nicola</au><au>Cinzia, Costa</au><au>Tedesco, Maria Giovanna</au><au>Harrison, Rachel E.</au><au>Bouman, Arjan</au><au>Palen, Emily</au><au>Challman, Thomas D.</au><au>Willemsen, Marjolein H.</au><au>Vogt, Julie</au><au>Cunniff, Christopher</au><au>Bergstrom, Katherine</au><au>Walia, Jagdeep S.</au><au>Bruel, Ange‐Line</au><au>Kini, Usha</au><au>Alkuraya, Fowzan S.</au><au>Slegesky, Valerie</au><au>Meeks, Naomi</au><au>Girotto, Paula</au><au>Johnson, Diana</au><au>Newbury‐Ecob, Ruth</au><au>Ockeloen, Charlotte W.</au><au>Prontera, Paolo</au><au>Lynch, Sally Ann</au><au>Li, Dong</au><au>Graham, John M.</au><au>Balasubramanian, Meena</au><aucorp>DDD Study</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3</atitle><jtitle>American journal of medical genetics. Part A</jtitle><addtitle>Am J Med Genet A</addtitle><date>2021-11</date><risdate>2021</risdate><volume>185</volume><issue>11</issue><spage>3446</spage><epage>3458</epage><pages>3446-3458</pages><issn>1552-4825</issn><eissn>1552-4833</eissn><abstract>The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>34436830</pmid><doi>10.1002/ajmg.a.62465</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-9194-0644</orcidid><orcidid>https://orcid.org/0000-0002-4482-6504</orcidid><orcidid>https://orcid.org/0000-0003-4158-341X</orcidid><orcidid>https://orcid.org/0000-0003-4960-9223</orcidid><orcidid>https://orcid.org/0000-0001-9602-4063</orcidid><orcidid>https://orcid.org/0000-0002-2265-6727</orcidid><orcidid>https://orcid.org/0000-0002-0526-465X</orcidid><orcidid>https://orcid.org/0000-0002-6041-477X</orcidid><orcidid>https://orcid.org/0000-0003-4906-7428</orcidid><orcidid>https://orcid.org/0000-0003-4297-1078</orcidid><orcidid>https://orcid.org/0000-0001-7663-1851</orcidid><orcidid>https://orcid.org/0000-0003-3531-5136</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1552-4825 |
| ispartof | American journal of medical genetics. Part A, 2021-11, Vol.185 (11), p.3446-3458 |
| issn | 1552-4825 1552-4833 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2564948767 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adolescent Adult ASXL3 ASXL3‐related syndrome Bainbridge–Ropers syndrome BRPS Child Child, Preschool Developmental Disabilities - epidemiology Developmental Disabilities - genetics Developmental Disabilities - physiopathology Female Genetic Predisposition to Disease Genetic Variation - genetics Genotype & phenotype Humans Hypertelorism - genetics Hypertelorism - physiopathology intellectual disability Intellectual Disability - genetics Intellectual Disability - physiopathology Male Muscle Hypotonia - genetics Muscle Hypotonia - physiopathology Mutation - genetics Neurodevelopmental disorders Neurodevelopmental Disorders - epidemiology Neurodevelopmental Disorders - genetics Neurodevelopmental Disorders - physiopathology Phenotype Phenotypes speech impairment Transcription Factors - genetics Young Adult |
| title | Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-26T05%3A24%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Expanding%20the%20phenotype%20of%20ASXL3%E2%80%90related%20syndrome:%20A%20comprehensive%20description%20of%2045%20unpublished%20individuals%20with%20inherited%20and%20de%20novo%20pathogenic%20variants%20in%20ASXL3&rft.jtitle=American%20journal%20of%20medical%20genetics.%20Part%20A&rft.au=Schirwani,%20Schaida&rft.aucorp=DDD%20Study&rft.date=2021-11&rft.volume=185&rft.issue=11&rft.spage=3446&rft.epage=3458&rft.pages=3446-3458&rft.issn=1552-4825&rft.eissn=1552-4833&rft_id=info:doi/10.1002/ajmg.a.62465&rft_dat=%3Cproquest_cross%3E2582283805%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2582283805&rft_id=info:pmid/34436830&rfr_iscdi=true |