Genomics is increasingly being incorporated into models of care for cancer. Understanding the ethical, legal, and social issues (ELSI) in this domain is important for successful and equitable implementation. We aimed to identify ELSI scholarship specific to cancer control and genomics. To do this, we undertook a scoping literature review and narrative synthesis, identifying 46 articles that met inclusion criteria. Eighteen ELSI themes were developed, including (1) equity of access, which included structural barriers to testing and research, access to preventive and follow-up care, and engagement with health systems; (2) family considerations, such as an ethical obligation to disseminate relevant genomic information to at-risk family members; (3) legal considerations, including privacy and confidentiality, genetic discrimination, and the prospective duty to reclassify variants; and (4) optimizing consent processes in clinical care and research. Gaps in the literature were identified with respect to equity for people living in rural or remote areas, and how to provide ethical care within culturally, linguistically, and ethnically diverse communities, including First Nations peoples. Our findings suggest a need for a multidisciplinary approach to examining ELSI in cancer genomics beyond initial test indication and within the broader context of the mainstreaming of genomics in health care.
{"title":"Ethical, legal, and social issues related to genetics and genomics in cancer: A scoping review and narrative synthesis","authors":"Amelia K. Smit , Akira Gokoolparsadh , Rebekah McWhirter , Lyndsay Newett , Vivienne Milch , Azure Hermes , Aideen McInerney-Leo , Ainsley J. Newson","doi":"10.1016/j.gim.2024.101270","DOIUrl":"10.1016/j.gim.2024.101270","url":null,"abstract":"<div><div>Genomics is increasingly being incorporated into models of care for cancer. Understanding the ethical, legal, and social issues (ELSI) in this domain is important for successful and equitable implementation. We aimed to identify ELSI scholarship specific to cancer control and genomics. To do this, we undertook a scoping literature review and narrative synthesis, identifying 46 articles that met inclusion criteria. Eighteen ELSI themes were developed, including (1) equity of access, which included structural barriers to testing and research, access to preventive and follow-up care, and engagement with health systems; (2) family considerations, such as an ethical obligation to disseminate relevant genomic information to at-risk family members; (3) legal considerations, including privacy and confidentiality, genetic discrimination, and the prospective duty to reclassify variants; and (4) optimizing consent processes in clinical care and research. Gaps in the literature were identified with respect to equity for people living in rural or remote areas, and how to provide ethical care within culturally, linguistically, and ethnically diverse communities, including First Nations peoples. Our findings suggest a need for a multidisciplinary approach to examining ELSI in cancer genomics beyond initial test indication and within the broader context of the mainstreaming of genomics in health care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101270"},"PeriodicalIF":6.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.gim.2024.101251
Elisa Cali,Tania Quirin,Clarissa Rocca,Stephanie Efthymiou,Antonella Riva,Dana Marafi,Maha S Zaki,Mohnish Suri,Roberto Dominguez,Hasnaa M Elbendary,Shahryar Alavi,Mohamed S Abdel-Hamid,Heba Morsy,Frederic Tran Mau-Them,Mathilde Nizon,Pavel Tesner,Lukáš Ryba,Faisal Zafar,Nuzhat Rana,Nebal W Saadi,Zahra Firoozfar,Pinar Gencpinar,Bulent Unay,Canan Ustun,Ange-Line Bruel,Christine Coubes,Jennifer Stefanich,Ozlem Sezer,Emanuele Agolini,Antonio Novelli,Gessica Vasco,Donatella Lettori,Mathieu Milh,Laurent Villard,Shimriet Zeidler,Henry Opperman,Vincent Strehlow,Mahmoud Y Issa,Hebatallah El Khassab,Prem Chand,Shahnaz Ibrahim,Ali Nejad-Rashidi,Mohammad Miryounesi,Pegah Larki,Jennifer Morrison,Ingrid Cristian,Isabelle Thiffault,Nicole L Bertsch,Grace J Noh,John Pappas,Ellen Moran,Nikolaos M Marinakis,Joanne Traeger-Synodinos,Susan Hosseini,Mohammad Reza Abbaszadegan,Roseline Caumes,Lisenka E L M Vissers,Maedeh Neshatdoust,Mostafa Zohour Montazer,Elmostafa El Fahime,Christin Canavati,Lara Kamal,Moien Kanaan,Omar Askander,Victoria Voinova,Olga Levchenko,Shahzhad Haider,Sara S Halbach,Elias Rayana Maia,Salehi Mansoor,Jain Vivek,Sanjukta Tawde,Viveka Santhosh R Challa,Vykuntaraju K Gowda,Varunvenkat M Srinivasan,Lucas Alves Victor,Benito Pinero-Banos,Jennifer Hague,Heba Ahmed Ei-Awady,Adelia Maria de Miranda Henriques-Souza,Huma Arshad Cheema,Muhammad Nadeem Anjum,Sara Idkaidak,Firas Alqarajeh,Osama Atawneh,Hagar Mor-Shaked,Tamar Harel,Giovanni Zifarelli,Peter Bauer,Fernando Kok,Joao Paulo Kitajima,Fabiola Monteiro,Juliana Josahkian,Gaetan Lesca,Nicolas Chatron,Dorothe Ville,David Murphy,Jeffrey L Neul,Sureni V Mullegama,Amber Begtrup,Isabella Herman,Tadahiro Mitani,Jennifer E Posey,Chee Geap Tay,Iram Javed,Lucinda Carr,Farah Kanani,Fiona Beecroft,Lee Hane,Elsayed Abdelkreem,Milan Macek,Luciana Bispo,Marwa Abd Elmaksoud,Farzad Hashemi-Gorji,Davut Pehlivan,David J Amor,Rami Abou Jamra,Wendy K Chung,Eshan Karimiani Ghayoor,Philippe Campeau,Fowzan S Alkuraya,Alistair T Pagnamenta,Joseph Gleeson,James R Lupski,Pasquale Striano,Andres Moreno-De-Luca,Denis L J Lafontaine,Henry Houlden,Reza Maroofian
PURPOSEThis study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.METHODSWe identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.RESULTSBiallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing.CONCLUSIONThis study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.
{"title":"Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.","authors":"Elisa Cali,Tania Quirin,Clarissa Rocca,Stephanie Efthymiou,Antonella Riva,Dana Marafi,Maha S Zaki,Mohnish Suri,Roberto Dominguez,Hasnaa M Elbendary,Shahryar Alavi,Mohamed S Abdel-Hamid,Heba Morsy,Frederic Tran Mau-Them,Mathilde Nizon,Pavel Tesner,Lukáš Ryba,Faisal Zafar,Nuzhat Rana,Nebal W Saadi,Zahra Firoozfar,Pinar Gencpinar,Bulent Unay,Canan Ustun,Ange-Line Bruel,Christine Coubes,Jennifer Stefanich,Ozlem Sezer,Emanuele Agolini,Antonio Novelli,Gessica Vasco,Donatella Lettori,Mathieu Milh,Laurent Villard,Shimriet Zeidler,Henry Opperman,Vincent Strehlow,Mahmoud Y Issa,Hebatallah El Khassab,Prem Chand,Shahnaz Ibrahim,Ali Nejad-Rashidi,Mohammad Miryounesi,Pegah Larki,Jennifer Morrison,Ingrid Cristian,Isabelle Thiffault,Nicole L Bertsch,Grace J Noh,John Pappas,Ellen Moran,Nikolaos M Marinakis,Joanne Traeger-Synodinos,Susan Hosseini,Mohammad Reza Abbaszadegan,Roseline Caumes,Lisenka E L M Vissers,Maedeh Neshatdoust,Mostafa Zohour Montazer,Elmostafa El Fahime,Christin Canavati,Lara Kamal,Moien Kanaan,Omar Askander,Victoria Voinova,Olga Levchenko,Shahzhad Haider,Sara S Halbach,Elias Rayana Maia,Salehi Mansoor,Jain Vivek,Sanjukta Tawde,Viveka Santhosh R Challa,Vykuntaraju K Gowda,Varunvenkat M Srinivasan,Lucas Alves Victor,Benito Pinero-Banos,Jennifer Hague,Heba Ahmed Ei-Awady,Adelia Maria de Miranda Henriques-Souza,Huma Arshad Cheema,Muhammad Nadeem Anjum,Sara Idkaidak,Firas Alqarajeh,Osama Atawneh,Hagar Mor-Shaked,Tamar Harel,Giovanni Zifarelli,Peter Bauer,Fernando Kok,Joao Paulo Kitajima,Fabiola Monteiro,Juliana Josahkian,Gaetan Lesca,Nicolas Chatron,Dorothe Ville,David Murphy,Jeffrey L Neul,Sureni V Mullegama,Amber Begtrup,Isabella Herman,Tadahiro Mitani,Jennifer E Posey,Chee Geap Tay,Iram Javed,Lucinda Carr,Farah Kanani,Fiona Beecroft,Lee Hane,Elsayed Abdelkreem,Milan Macek,Luciana Bispo,Marwa Abd Elmaksoud,Farzad Hashemi-Gorji,Davut Pehlivan,David J Amor,Rami Abou Jamra,Wendy K Chung,Eshan Karimiani Ghayoor,Philippe Campeau,Fowzan S Alkuraya,Alistair T Pagnamenta,Joseph Gleeson,James R Lupski,Pasquale Striano,Andres Moreno-De-Luca,Denis L J Lafontaine,Henry Houlden,Reza Maroofian","doi":"10.1016/j.gim.2024.101251","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101251","url":null,"abstract":"PURPOSEThis study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.METHODSWe identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.RESULTSBiallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing.CONCLUSIONThis study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"1 1","pages":"101251"},"PeriodicalIF":8.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.gim.2024.101266
Clémence Vanlerberghe , Frédéric Frénois , Thomas Smol , Anne-Sophie Jourdain , Fabienne Escande , Emilie Aït-Yahya , Abdulrahman A. Aldeeri , Timothy W. Yu , Valérie Cormier-Daire , Jamal Ghoumid , Maureen Jacob , Ruth Newbury-Ecob , Sylvie Manouvrier , Jessica Platon , Sebastian Sailer , Perrine Brunelle , Lydie Da Costa , Florence Petit
Purpose
Diamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition.
Methods
Patients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34+ cells were studied by flow cytometry, and RPL26 expression by quantitative reverse transcription polymerase chain reaction and immunoblotting.
Results
We report on 8 affected patients from 4 families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes.
Conclusion
We confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease.
{"title":"RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront","authors":"Clémence Vanlerberghe , Frédéric Frénois , Thomas Smol , Anne-Sophie Jourdain , Fabienne Escande , Emilie Aït-Yahya , Abdulrahman A. Aldeeri , Timothy W. Yu , Valérie Cormier-Daire , Jamal Ghoumid , Maureen Jacob , Ruth Newbury-Ecob , Sylvie Manouvrier , Jessica Platon , Sebastian Sailer , Perrine Brunelle , Lydie Da Costa , Florence Petit","doi":"10.1016/j.gim.2024.101266","DOIUrl":"10.1016/j.gim.2024.101266","url":null,"abstract":"<div><h3>Purpose</h3><div>Diamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. <em>RPL26</em> (ribosomal protein <em>L26</em>) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition.</div></div><div><h3>Methods</h3><div>Patients carrying heterozygous <em>RPL26</em> variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34<sup>+</sup> cells were studied by flow cytometry, and <em>RPL26</em> expression by quantitative reverse transcription polymerase chain reaction and immunoblotting.</div></div><div><h3>Results</h3><div>We report on 8 affected patients from 4 families. Detailed phenotyping reveals that <em>RPL26</em> is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that <em>RPL26</em> haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes.</div></div><div><h3>Conclusion</h3><div>We confirm <em>RPL26</em> as a DBS gene and expand the phenotypic spectrum of the gene and the disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101266"},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.gim.2024.101267
Clémence Vanlerberghe , Anne Sophie Jourdain , Frédéric Frenois , Emilie Ait-Yahya , Mike Bamshad , Anne Dieux , William Dufour , Fiona Leduc , Sylvie Manouvrier-Hanu , Karynne Patterson , Jamal Ghoumid , Fabienne Escande , Thomas Smol , Perrine Brunelle , Florence Petit
Purpose
Predicting effects of genomic variants has become a real challenge in the diagnosis of rare human diseases. Holt-Oram syndrome is an autosomal condition characterized by the association of radial and heart defects, due to variants in TBX5. Most variants are predicted to be truncating and result in haploinsufficiency. The pathogenicity of missense or splice variants is harder to demonstrate.
Methods
Fourteen TBX5 variants of uncertain significance (5 missense, 9 splice) and 6 likely pathogenic missense variants were selected for functional testing, depending on the variant-type (immunolocalization, western blot, reporter assays, minigene splice assays, and reverse transcription-polymerase chain reaction). Results were compared with in silico predictions.
Results
Functional tests allowed to reclassify 9/14 variants of uncertain significance in TBX5 as likely pathogenic, confirming their role in Holt-Oram syndrome. We demonstrated loss of function (n = 8) or gain of function (n = 1) for 9 of the 11 missense variants, whereas no functional impact was shown for the 2 variants: p.(Gly195Ala) and p.(Ser261Cys), as suggested by contradictory predictions of in silico approaches. Of 9 splice variants predicted to affect splicing by SpliceAI, we observed partial or complete exon skipping (n = 6), intron retention (n = 2) or exon shortening (n = 1), inducing frame shifting with premature stop codons.
Conclusion
Bioinformatic and biological approaches are complementary, together with a good knowledge of clinical conditions, for accurate American College of Medical Genetics and Genomics classification in human rare diseases.
{"title":"Functional characterization vs in silico prediction for TBX5 missense and splice variants in Holt-Oram syndrome","authors":"Clémence Vanlerberghe , Anne Sophie Jourdain , Frédéric Frenois , Emilie Ait-Yahya , Mike Bamshad , Anne Dieux , William Dufour , Fiona Leduc , Sylvie Manouvrier-Hanu , Karynne Patterson , Jamal Ghoumid , Fabienne Escande , Thomas Smol , Perrine Brunelle , Florence Petit","doi":"10.1016/j.gim.2024.101267","DOIUrl":"10.1016/j.gim.2024.101267","url":null,"abstract":"<div><h3>Purpose</h3><div>Predicting effects of genomic variants has become a real challenge in the diagnosis of rare human diseases. Holt-Oram syndrome is an autosomal condition characterized by the association of radial and heart defects, due to variants in <em>TBX5</em>. Most variants are predicted to be truncating and result in haploinsufficiency. The pathogenicity of missense or splice variants is harder to demonstrate.</div></div><div><h3>Methods</h3><div>Fourteen <em>TBX5</em> variants of uncertain significance (5 missense, 9 splice) and 6 likely pathogenic missense variants were selected for functional testing, depending on the variant-type (immunolocalization, western blot, reporter assays, minigene splice assays, and reverse transcription-polymerase chain reaction). Results were compared with <em>in silico</em> predictions.</div></div><div><h3>Results</h3><div>Functional tests allowed to reclassify 9/14 variants of uncertain significance in <em>TBX5</em> as likely pathogenic, confirming their role in Holt-Oram syndrome. We demonstrated loss of function (<em>n</em> = 8) or gain of function (<em>n</em> = 1) for 9 of the 11 missense variants, whereas no functional impact was shown for the 2 variants: p.(Gly195Ala) and p.(Ser261Cys), as suggested by contradictory predictions of <em>in silico</em> approaches. Of 9 splice variants predicted to affect splicing by SpliceAI, we observed partial or complete exon skipping (<em>n</em> = 6), intron retention (<em>n</em> = 2) or exon shortening (<em>n</em> = 1), inducing frame shifting with premature stop codons.</div></div><div><h3>Conclusion</h3><div>Bioinformatic and biological approaches are complementary, together with a good knowledge of clinical conditions, for accurate American College of Medical Genetics and Genomics classification in human rare diseases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101267"},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.gim.2024.101254
Wesley G. Patterson , Stephanie J. Offord , Laura D. Buch , Gina M. Lewis , Ashley Andrews , Kaelyn B. Sparks , Jessica A. Cooley Coleman , Leta M. Tribble
Purpose
This study characterizes the current landscape of genetics advanced practice providers (APPs) in the United States.
Methods
A 35-question survey was emailed to the Genetics APP Listserv in the fall of 2023. Questions represented 5 domains: demographics, practice, onboarding, compensation, and perceptions.
Results
A total of 105 genetics APPs (93%) completed the survey. Genetics APPs evaluate various patient types and populations in multiple settings, working an average of 41.3 hours and seeing 15 patients weekly. Nearly all see new (96%) and follow-up (98%) patients and utilize telemedicine (93%). Half (51%) have only worked in the genetics specialty during their career. Overall, APPs are generally satisfied with their career as a genetics APP (98%) and work-life balance (86%), and most (86%) feel that they function at the top of their scope.
Conclusion
Study findings elucidate the current state of genetics APPs. Results define the characteristics and role of an APP in the genetics specialty and will guide employers and genetics organizations to utilize APPs at the top of their scope and recruit new APPs to this exciting field. A collaborative effort is needed to increase the overall genetics workforce, decrease patient wait times, and increase access to genetics care.
{"title":"Advanced practice providers in the medical genetics workforce: A nationwide survey","authors":"Wesley G. Patterson , Stephanie J. Offord , Laura D. Buch , Gina M. Lewis , Ashley Andrews , Kaelyn B. Sparks , Jessica A. Cooley Coleman , Leta M. Tribble","doi":"10.1016/j.gim.2024.101254","DOIUrl":"10.1016/j.gim.2024.101254","url":null,"abstract":"<div><h3>Purpose</h3><div>This study characterizes the current landscape of genetics advanced practice providers (APPs) in the United States.</div></div><div><h3>Methods</h3><div>A 35-question survey was emailed to the Genetics APP Listserv in the fall of 2023. Questions represented 5 domains: demographics, practice, onboarding, compensation, and perceptions.</div></div><div><h3>Results</h3><div>A total of 105 genetics APPs (93%) completed the survey. Genetics APPs evaluate various patient types and populations in multiple settings, working an average of 41.3 hours and seeing 15 patients weekly. Nearly all see new (96%) and follow-up (98%) patients and utilize telemedicine (93%). Half (51%) have only worked in the genetics specialty during their career. Overall, APPs are generally satisfied with their career as a genetics APP (98%) and work-life balance (86%), and most (86%) feel that they function at the top of their scope.</div></div><div><h3>Conclusion</h3><div>Study findings elucidate the current state of genetics APPs. Results define the characteristics and role of an APP in the genetics specialty and will guide employers and genetics organizations to utilize APPs at the top of their scope and recruit new APPs to this exciting field. A collaborative effort is needed to increase the overall genetics workforce, decrease patient wait times, and increase access to genetics care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101254"},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.gim.2024.101250
S.B.B. Bon , R.H.P. Wouters , J.J. Bakhuizen , M.M. van den Heuvel-Eibrink , H. Maurice-Stam , M.C.J. Jongmans , M.A. Grootenhuis
Purpose
Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored.
Methods
Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries.
Results
Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires, whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries.
Conclusion
Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.
{"title":"Parents' experiences with sequencing of all known pediatric cancer predisposition genes in children with cancer","authors":"S.B.B. Bon , R.H.P. Wouters , J.J. Bakhuizen , M.M. van den Heuvel-Eibrink , H. Maurice-Stam , M.C.J. Jongmans , M.A. Grootenhuis","doi":"10.1016/j.gim.2024.101250","DOIUrl":"10.1016/j.gim.2024.101250","url":null,"abstract":"<div><h3>Purpose</h3><div>Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored.</div></div><div><h3>Methods</h3><div>Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries.</div></div><div><h3>Results</h3><div>Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires, whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries.</div></div><div><h3>Conclusion</h3><div>Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101250"},"PeriodicalIF":6.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Health care fraud comprises a sizable portion of United States health care expenditure and inflicts undue burden on payors, patients, and the health care system overall. The genetic testing industry is rapidly growing, which propagates opportunities for health care fraud. Although federal organizations have highlighted it as an issue, there is limited research exploring genetic testing fraud.
Methods
A retrospective review of federal websites, news articles, and a legal database resulted in 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis.
Results
Themes of fraudulent activity included submission of fraudulent claims, kickback or bribe payments, minimal or no contact with patients for whom testing was ordered, inappropriate billing and documentation practices, and further actions to conceal fraud. Repercussions imposed on defendants included monetary penalty, imprisonment, business restrictions, and seizure of property.
Conclusion
High rates of medically inappropriate testing in fraud cases highlight the value of genetics experts in ordering or reviewing claims for genetic testing. Examining fraudulent activity in genetic testing can help providers identify and report fraud and provide awareness of optimal health care allocation in the genetic testing industry.
{"title":"Fraud in genetic testing: Swindling the system","authors":"Rachel Notestine , Claire N. Singletary , Meagan Choates , Stephanie Gandomi , Molly Daniels , Rebecca Lunstroth , Quinn Stein","doi":"10.1016/j.gim.2024.101248","DOIUrl":"10.1016/j.gim.2024.101248","url":null,"abstract":"<div><h3>Purpose</h3><div>Health care fraud comprises a sizable portion of United States health care expenditure and inflicts undue burden on payors, patients, and the health care system overall. The genetic testing industry is rapidly growing, which propagates opportunities for health care fraud. Although federal organizations have highlighted it as an issue, there is limited research exploring genetic testing fraud.</div></div><div><h3>Methods</h3><div>A retrospective review of federal websites, news articles, and a legal database resulted in 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis.</div></div><div><h3>Results</h3><div>Themes of fraudulent activity included submission of fraudulent claims, kickback or bribe payments, minimal or no contact with patients for whom testing was ordered, inappropriate billing and documentation practices, and further actions to conceal fraud. Repercussions imposed on defendants included monetary penalty, imprisonment, business restrictions, and seizure of property.</div></div><div><h3>Conclusion</h3><div>High rates of medically inappropriate testing in fraud cases highlight the value of genetics experts in ordering or reviewing claims for genetic testing. Examining fraudulent activity in genetic testing can help providers identify and report fraud and provide awareness of optimal health care allocation in the genetic testing industry.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101248"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.gim.2024.101247
Jennifer Micham , Marshall Summar , Debra Regier , Colleen Lawrence , Deepika Burkardt
{"title":"Correspondence on “The Clinical Geneticist Workforce: Community Forums to Address Challenges and Opportunities” by Chung et al","authors":"Jennifer Micham , Marshall Summar , Debra Regier , Colleen Lawrence , Deepika Burkardt","doi":"10.1016/j.gim.2024.101247","DOIUrl":"10.1016/j.gim.2024.101247","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101247"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.gim.2024.101249
Jenny Lord , Carolina J. Oquendo , Htoo A. Wai , John G. Holloway , Alexandra Martin-Geary , Alexander J.M. Blakes , Elena Arciero , Silvia Domcke , Anne-Marie Childs , Karen Low , Julia Rankin , Genomics England Research Consortium, Diana Baralle , Hilary C. Martin , Nicola Whiffin
Purpose
Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in trans with these is unknown.
Methods
In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.
Results
We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further 3 (PAH, LAMA2, and IGHMBP2).
Conclusion
We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.
{"title":"Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants","authors":"Jenny Lord , Carolina J. Oquendo , Htoo A. Wai , John G. Holloway , Alexandra Martin-Geary , Alexander J.M. Blakes , Elena Arciero , Silvia Domcke , Anne-Marie Childs , Karen Low , Julia Rankin , Genomics England Research Consortium, Diana Baralle , Hilary C. Martin , Nicola Whiffin","doi":"10.1016/j.gim.2024.101249","DOIUrl":"10.1016/j.gim.2024.101249","url":null,"abstract":"<div><h3>Purpose</h3><div>Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in <em>trans</em> with these is unknown.</div></div><div><h3>Methods</h3><div>In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.</div></div><div><h3>Results</h3><div>We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in <em>GAA</em>, <em>NPHP3</em>, and <em>PKHD1</em>) and candidate diagnoses in a further 3 (<em>PAH, LAMA2,</em> and <em>IGHMBP2)</em>.</div></div><div><h3>Conclusion</h3><div>We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101249"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-10DOI: 10.1016/j.gim.2024.101239
Jessica Dawson , Chris Kay , Hailey Findlay Black , Stephanie Bortnick , Kyla Javier , Qingwen Xia , Akshdeep Sandhu , Christina Buchanan , Virginia Hogg , Florence C.F. Chang , Jun Goto , Larissa Arning , Carsten Saft , Emilia K. Bijlsma , Huu P. Nguyen , Richard Roxburgh , Michael R. Hayden
Purpose
To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).
Methods
We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.
Results
Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range.
Conclusion
Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.
目的：确定亨廷顿病（HD）患者队列中 HTT CAG 和 CCG 重复序列的中断缺失（LOI）和中断重复（DOI）修饰变异的频率及其临床影响：我们对来自 UBC HD 生物库和五个研究机构的有症状 HD 患者进行了序列变异筛选。方法：我们从 UBC HD 生物库和五个研究机构中筛选有症状的 HD 患者，寻找序列变异。在确定变异后，我们研究了变异对临床的影响以及在穿透性降低范围内的频率：结果：具有 CAG-CCG LOI 和 CCG LOI 变体的参与者患 HD 的时间相近，都提前了 12.5 年。序列变异表现出祖先特异性差异。具有 CAG-CCG LOI 变体的患者 TMS 的进展也较快，每年增加 1.9 个单位。有症状的 CAG-CCG LOI 变体参与者在穿透性降低的范围内表现出富集性。CAG-CCG LOI变异可解释两名诊断重复序列低于致病范围的无症状HD患者的发病原因：我们的研究结果对具有 CAG-CCG LOI 变异的参与者具有重要的临床意义，因为他们在诊断临界范围附近得到了不准确的诊断。这些人需要改进诊断测试方法和临床管理。我们展示了最大、最多样化的 HTT CAG 和 CCG 序列变异群，并强调了它们在 HD 临床表现中的重要性。
{"title":"The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort","authors":"Jessica Dawson , Chris Kay , Hailey Findlay Black , Stephanie Bortnick , Kyla Javier , Qingwen Xia , Akshdeep Sandhu , Christina Buchanan , Virginia Hogg , Florence C.F. Chang , Jun Goto , Larissa Arning , Carsten Saft , Emilia K. Bijlsma , Huu P. Nguyen , Richard Roxburgh , Michael R. Hayden","doi":"10.1016/j.gim.2024.101239","DOIUrl":"10.1016/j.gim.2024.101239","url":null,"abstract":"<div><h3>Purpose</h3><p>To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the <em>HTT</em> CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).</p></div><div><h3>Methods</h3><p>We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.</p></div><div><h3>Results</h3><p>Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range.</p></div><div><h3>Conclusion</h3><p>Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse <em>HTT</em> CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101239"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001734/pdfft?md5=1abcca0080b367715dc410d73f51671a&pid=1-s2.0-S1098360024001734-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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