Pub Date : 2025-02-01DOI: 10.1016/j.gim.2024.101305
Alice Garrett , Sophie Allen , Miranda Durkie , George J. Burghel , Rachel Robinson , Alison Callaway , Joanne Field , Bethan Frugtniet , Sheila Palmer-Smith , Jonathan Grant , Judith Pagan , Trudi McDevitt , Charlie F. Rowlands , Terri McVeigh , Helen Hanson , Clare Turnbull
Purpose
Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.
Methods
A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group.
Results
CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data.
Conclusion
CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.
{"title":"Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)","authors":"Alice Garrett , Sophie Allen , Miranda Durkie , George J. Burghel , Rachel Robinson , Alison Callaway , Joanne Field , Bethan Frugtniet , Sheila Palmer-Smith , Jonathan Grant , Judith Pagan , Trudi McDevitt , Charlie F. Rowlands , Terri McVeigh , Helen Hanson , Clare Turnbull","doi":"10.1016/j.gim.2024.101305","DOIUrl":"10.1016/j.gim.2024.101305","url":null,"abstract":"<div><h3>Purpose</h3><div>Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.</div></div><div><h3>Methods</h3><div>A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group.</div></div><div><h3>Results</h3><div>CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data.</div></div><div><h3>Conclusion</h3><div>CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101305"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567117","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101323
Chloe Mighton , Rita Kodida , Salma Shickh , Marc Clausen , Emma Reble , Jordan Sam , Sonya Grewal , Daena Hirjikaka , Seema Panchal , Carolyn Piccinin , Melyssa Aronson , Thomas Ward , Susan Randall Armel , Renee Hofstedter , Tracy Graham , Talia Mancuso , Nicole Forster , José-Mario Capo-Chichi , Elena Greenfeld , Abdul Noor , Kevin E. Thorpe
Purpose
Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants’ clinical features and family history.
Methods
Adult cancer patients had exome sequencing with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.
Results
All participants (n = 139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the American College of Medical Genetics and Genomics list (v3.2, noncancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.
Conclusion
Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.
{"title":"Opportunistic genomic screening has clinical utility: An interventional cohort study","authors":"Chloe Mighton , Rita Kodida , Salma Shickh , Marc Clausen , Emma Reble , Jordan Sam , Sonya Grewal , Daena Hirjikaka , Seema Panchal , Carolyn Piccinin , Melyssa Aronson , Thomas Ward , Susan Randall Armel , Renee Hofstedter , Tracy Graham , Talia Mancuso , Nicole Forster , José-Mario Capo-Chichi , Elena Greenfeld , Abdul Noor , Kevin E. Thorpe","doi":"10.1016/j.gim.2024.101323","DOIUrl":"10.1016/j.gim.2024.101323","url":null,"abstract":"<div><h3>Purpose</h3><div>Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants’ clinical features and family history.</div></div><div><h3>Methods</h3><div>Adult cancer patients had exome sequencing with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.</div></div><div><h3>Results</h3><div>All participants (<em>n</em> = 139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the American College of Medical Genetics and Genomics list (v3.2, noncancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.</div></div><div><h3>Conclusion</h3><div>Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101323"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618584","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101332
Shenali Anne Amaratunga , Tara Hussein Tayeb , Petra Dusatkova , Lenka Elblova , Jana Drabova , Lukas Plachy , Stepanka Pruhova , Jan Lebl
Purpose
Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations.
Methods
Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ −2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS.
Results
A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases.
Conclusion
A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
导言：近亲结婚家族的基因检测有助于全面了解病理生理途径。然而，身材矮小（SS）遗传学在确定的近亲群中仍未得到探索。本研究对伊拉克苏莱曼尼一个独特的儿科队列进行了研究，旨在为类似人群的基因检测算法提供启发：在 2018-2020 年转诊的 280 名 SS 中，64 名儿童符合纳入标准（来自近亲结婚家庭；身高≤-2.25 SD），51 名儿童提供了知情同意书（30 名女性；31 名综合征 SS）并接受了调查，主要是通过外显子组测序。根据 ACMG 标准对优先考虑的变异进行了评估。通过将我们的研究结果与已发表的 SS 基因面板并列，进行了比较分析：结果：31/51（61%）名参与者阐明了 SS 的遗传原因。在涉及 GH-IGF-1 轴（GHR、SOX3）、甲状腺轴（TSHR）、生长板（CTSK、COL1A2、COL10A1、DYM、FN1、LTBP3、MMP13、NPR2、SHOX）、信号转导（PTPN11）的基因中发现了致病变体、DNA/RNA复制（DNAJC21、GZF1、LIG4）、细胞骨架结构（CCDC8、FLNA、PCNT）、跨膜运输（SLC34A3、SLC7A7）、酶编码（CYP27B1、GALNS、GNPTG）和纤毛生成（CFAP410）。另有两名参与者患有 Silver-Russell 综合征，一人患有 del22q.11.21。综合征 SS 对确定单基因疾病具有预测性。使用基因面板只能在 10-33% 的病例中得出阳性结果：结论：量身定制的检测策略对于提高近亲繁殖的 SS 儿童的诊断率至关重要。
{"title":"High yield of monogenic short stature in children from Kurdistan, Iraq: A genetic testing algorithm for consanguineous families","authors":"Shenali Anne Amaratunga , Tara Hussein Tayeb , Petra Dusatkova , Lenka Elblova , Jana Drabova , Lukas Plachy , Stepanka Pruhova , Jan Lebl","doi":"10.1016/j.gim.2024.101332","DOIUrl":"10.1016/j.gim.2024.101332","url":null,"abstract":"<div><h3>Purpose</h3><div>Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations.</div></div><div><h3>Methods</h3><div>Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ −2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS.</div></div><div><h3>Results</h3><div>A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (<em>GHR</em> and <em>SOX3</em>), thyroid axis (<em>TSHR</em>), growth plate (<em>CTSK</em>, <em>COL1A2</em>, <em>COL10A1</em>, <em>DYM</em>, <em>FN1</em>, <em>LTBP3</em>, <em>MMP13</em>, <em>NPR2</em>, and <em>SHOX</em>), signal transduction (<em>PTPN11</em>), DNA/RNA replication (<em>DNAJC21</em>, <em>GZF1</em>, and <em>LIG4)</em>, cytoskeletal structure (<em>CCDC8</em>, <em>FLNA</em>, and <em>PCNT</em>), transmembrane transport (<em>SLC34A3</em> and <em>SLC7A7</em>), enzyme coding (<em>CYP27B1</em>, <em>GALNS</em>, and <em>GNPTG</em>), and ciliogenesis (<em>CFAP410</em>). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases.</div></div><div><h3>Conclusion</h3><div>A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101332"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709916","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101325
Cassie Houtz
{"title":"Response to Connolly et al","authors":"Cassie Houtz","doi":"10.1016/j.gim.2024.101325","DOIUrl":"10.1016/j.gim.2024.101325","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101325"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618587","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101330
Lisa F. Saba , Haley Streff , Dolores Lopez-Terrada , Jennifer Scull
Purpose
Exome sequencing (ES) and genome sequencing (GS) are useful tests to diagnose rare diseases in pediatric patients in critical care settings. Genomic test stewardship can increase the appropriate use of these tests leading to improved diagnostics and cost savings.
Methods
A mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics.
Results
There were 444 genetic test request orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval, leading to an overall cost savings of $345,821.00 or $778.88 per order. The combined diagnostic rate was 28.2% in this patient population.
Conclusion
Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve the appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.
{"title":"The “genetic test request”: A genomic stewardship intervention for inpatient exome and genome orders at a tertiary pediatric hospital","authors":"Lisa F. Saba , Haley Streff , Dolores Lopez-Terrada , Jennifer Scull","doi":"10.1016/j.gim.2024.101330","DOIUrl":"10.1016/j.gim.2024.101330","url":null,"abstract":"<div><h3>Purpose</h3><div>Exome sequencing (ES) and genome sequencing (GS) are useful tests to diagnose rare diseases in pediatric patients in critical care settings. Genomic test stewardship can increase the appropriate use of these tests leading to improved diagnostics and cost savings.</div></div><div><h3>Methods</h3><div>A mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics.</div></div><div><h3>Results</h3><div>There were 444 genetic test request orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval, leading to an overall cost savings of $345,821.00 or $778.88 per order. The combined diagnostic rate was 28.2% in this patient population.</div></div><div><h3>Conclusion</h3><div>Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve the appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101330"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667326","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101217
Alexandre Buffet , Mathilde Filser , Alexandra Bruel , Rodolphe Dard , Thibaud Quibel , Charlotte Dubucs , Theresa Kwon , Pauline Le Tanno , Julien Thevenon , Alban Ziegler , Lise Allard , Vincent Guigonis , Jean-Jacques Roux , Laurence Heidet , Claire Rougeulle , Olivia Boyer , Rosa Vargas-Poussou , Marguerite Hureaux
Purpose
Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women.
Methods
We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples.
Results
Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases, and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%), and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women.
Conclusion
This work enriches the phenotypic and genetic description of this recently described disease and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.
{"title":"X-linked transient antenatal Bartter syndrome related to MAGED2 gene: Enriching the phenotypic description and pathophysiologic investigation","authors":"Alexandre Buffet , Mathilde Filser , Alexandra Bruel , Rodolphe Dard , Thibaud Quibel , Charlotte Dubucs , Theresa Kwon , Pauline Le Tanno , Julien Thevenon , Alban Ziegler , Lise Allard , Vincent Guigonis , Jean-Jacques Roux , Laurence Heidet , Claire Rougeulle , Olivia Boyer , Rosa Vargas-Poussou , Marguerite Hureaux","doi":"10.1016/j.gim.2024.101217","DOIUrl":"10.1016/j.gim.2024.101217","url":null,"abstract":"<div><h3>Purpose</h3><div>Transient Bartter syndrome related to pathogenic variants of <em>MAGED2</em> is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women.</div></div><div><h3>Methods</h3><div>We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that <em>MAGED2</em> is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples.</div></div><div><h3>Results</h3><div>Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases, and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%), and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the <em>MAGED2</em> CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women.</div></div><div><h3>Conclusion</h3><div>This work enriches the phenotypic and genetic description of this recently described disease and deepens our understanding of the pathophysiological role and regulation of <em>MAGED2</em>. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101217"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733873","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101285
Shangqing Jiang , Gregory F. Guzauskas , Shawn Garbett , John A. Graves , Marc S. Williams , Jing Hao , Jinyi Zhu , Gail P. Jarvik , Josh J. Carlson , Josh F. Peterson , David L. Veenstra
Purpose
Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies.
Methods
We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions.
Results
Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles.
Conclusion
Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.
{"title":"Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening","authors":"Shangqing Jiang , Gregory F. Guzauskas , Shawn Garbett , John A. Graves , Marc S. Williams , Jing Hao , Jinyi Zhu , Gail P. Jarvik , Josh J. Carlson , Josh F. Peterson , David L. Veenstra","doi":"10.1016/j.gim.2024.101285","DOIUrl":"10.1016/j.gim.2024.101285","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies.</div></div><div><h3>Methods</h3><div>We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions.</div></div><div><h3>Results</h3><div>Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles.</div></div><div><h3>Conclusion</h3><div>Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101285"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365043","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 : 2025-02-01DOI: 10.1016/j.gim.2024.101329
Julie Wiedower , Hadley Stevens Smith , Christopher L. Farrell , Veronica Parker , Laura Rebek , Stephanie Clark Davis
Purpose
Health care stakeholders’ perspectives on the value of genomic testing vary widely and directly affect the access and practice of genomic medicine. To our knowledge, a review of US health care payers’ perspectives on genomic testing has not been performed.
Methods
We conducted a systematic literature review of US payers’ perspectives on genomic testing in the MEDLINE, PubMed, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records, and using the framework method, common domains were recorded.
Results
Domains included clinical utility, coverage decision frameworks, potential harms, costs, paying for research, demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous.
Conclusion
A deeper understanding of how payers approach genomic testing may allow comparison with other stakeholders’ perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.
{"title":"Payer perspectives on genomic testing in the United States: A systematic literature review","authors":"Julie Wiedower , Hadley Stevens Smith , Christopher L. Farrell , Veronica Parker , Laura Rebek , Stephanie Clark Davis","doi":"10.1016/j.gim.2024.101329","DOIUrl":"10.1016/j.gim.2024.101329","url":null,"abstract":"<div><h3>Purpose</h3><div>Health care stakeholders’ perspectives on the value of genomic testing vary widely and directly affect the access and practice of genomic medicine. To our knowledge, a review of US health care payers’ perspectives on genomic testing has not been performed.</div></div><div><h3>Methods</h3><div>We conducted a systematic literature review of US payers’ perspectives on genomic testing in the MEDLINE, PubMed, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records, and using the framework method, common domains were recorded.</div></div><div><h3>Results</h3><div>Domains included clinical utility, coverage decision frameworks, potential harms, costs, paying for research, demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous.</div></div><div><h3>Conclusion</h3><div>A deeper understanding of how payers approach genomic testing may allow comparison with other stakeholders’ perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101329"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667350","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 : 2025-01-31DOI: 10.1016/j.gim.2025.101368
Lucas J Matthews, Daphne O Martschenko, Colby Lewis V, Maya Sabatello
Purpose: Education is important for life-long skills and economic growth, but student placement decisions may be shaped by social biases. As genomic information captured via polygenic scores becomes more available, it may also inform student placement decisions. We assessed the intersectional effects of polygenic scores, race, disability, and socioeconomic status on US adults' views about educational trajectories using an online experimental survey design.
Methods: 1,367 US adults were randomized to one of 16 conditions and prompted to read a short vignette about a boy named "Michael," also depicted in an image. Each condition varied Michael's race (Black/White), disability (wheelchair-user/no), socioeconomic status (high/low), and polygenic score (high/low) for educational attainment (EA-PGS). After reading the vignette, respondents were asked to answer multi-choice questions about Michael's immediate and long-term educational trajectories.
Results: Variation in Michael's EA-PGS strongly influenced participants' expectations regarding: 1) the most appropriate immediate educational program for Michael (i.e., general, 'special', or gifted education); 2) whether he would graduate high school; and, if so, 3) the highest educational degree he would complete in his lifetime (Associates, Bachelors, Masters, or PhD). Across these responses, high EA-PGS was associated with more socially desirable outcomes and the opposite was the case for low EA-PGS. Depicting Michael in a wheelchair significantly influenced respondents' expectation that his most appropriate immediate educational trajectory would be 'special' education. There were significant interactions between Michael's race, disability, socioeconomic status, and EA-PGS.
Conclusion: Information about a child's EA-PGS may impact views about their immediate and long-term educational trajectories. The negative impacts of a low EA-PGS are comparable to the positive impacts of a high EA-PGS. EA-PGS may be interpreted in ways that compound existing stereotypes related to a child's race, disability, and socioeconomic status.
{"title":"Intersectionality in a Sociogenomic World: How do Race, Disability, Socioeconomic Status, and Polygenic Prediction Interact to Impact Perceptions of Educational Trajectories?","authors":"Lucas J Matthews, Daphne O Martschenko, Colby Lewis V, Maya Sabatello","doi":"10.1016/j.gim.2025.101368","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101368","url":null,"abstract":"<p><strong>Purpose: </strong>Education is important for life-long skills and economic growth, but student placement decisions may be shaped by social biases. As genomic information captured via polygenic scores becomes more available, it may also inform student placement decisions. We assessed the intersectional effects of polygenic scores, race, disability, and socioeconomic status on US adults' views about educational trajectories using an online experimental survey design.</p><p><strong>Methods: </strong>1,367 US adults were randomized to one of 16 conditions and prompted to read a short vignette about a boy named \"Michael,\" also depicted in an image. Each condition varied Michael's race (Black/White), disability (wheelchair-user/no), socioeconomic status (high/low), and polygenic score (high/low) for educational attainment (EA-PGS). After reading the vignette, respondents were asked to answer multi-choice questions about Michael's immediate and long-term educational trajectories.</p><p><strong>Results: </strong>Variation in Michael's EA-PGS strongly influenced participants' expectations regarding: 1) the most appropriate immediate educational program for Michael (i.e., general, 'special', or gifted education); 2) whether he would graduate high school; and, if so, 3) the highest educational degree he would complete in his lifetime (Associates, Bachelors, Masters, or PhD). Across these responses, high EA-PGS was associated with more socially desirable outcomes and the opposite was the case for low EA-PGS. Depicting Michael in a wheelchair significantly influenced respondents' expectation that his most appropriate immediate educational trajectory would be 'special' education. There were significant interactions between Michael's race, disability, socioeconomic status, and EA-PGS.</p><p><strong>Conclusion: </strong>Information about a child's EA-PGS may impact views about their immediate and long-term educational trajectories. The negative impacts of a low EA-PGS are comparable to the positive impacts of a high EA-PGS. EA-PGS may be interpreted in ways that compound existing stereotypes related to a child's race, disability, and socioeconomic status.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101368"},"PeriodicalIF":6.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122887","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 : 2025-01-29DOI: 10.1016/j.gim.2025.101371
Iva Strnadová, Manjekah Dunn, Chloe Molnar, Julie Loblinzk, Jackie Leach Scully, Joanne Danker, Michelle Tso, Tiffany Qing Lim, Yasmin Cathcart-King, Karen-Maia Jackaman, Sarah Hayes, Sierra Angelina Willow, Jackie Boyle, Jennifer Hansen, Skie Sarfaraz, Caroline Basckin, Celia Halliburton, Thulasee Sri Ganeshan, Edwina K Middleton, Bronwyn Terrill, Elizabeth Emma Palmer
Purpose: People with intellectual disability inequitably access high-quality genetic healthcare. Yet, they are keen to understand more about genetic healthcare and recommend clinicians need education on delivering more inclusive care and that multi-modal genetic health literacy resources should be co-produced.
Methods: Our inclusive research team applied best practice co-production principles to deliver a suite of resources, the GeneEQUAL Toolkit. Mixed-methods evaluation including surveys and a focus group/interviews assessed (i) clinicians' perceived capabilities, motivation, and opportunities for providing inclusive healthcare for people with intellectual disability before and after exploring the Toolkit; (ii) the perceptions and opinions of people with intellectual disability about the Toolkit; (iii) the reach of the Toolkit components; and (iv) the reflections of people with intellectual disability and clinicians on the co-production process.
Results: The Toolkit met the expectations and preferences of people with intellectual disability and clinicians and had global reach. Co-production was feasible and judged critical for the high value of the Toolkit, in motivating clinicians to change their clinical practice and empowering people with intellectual disability.
Conclusion: Co-production can be successfully applied to improve the engagement of people with intellectual disability and potentially reduce health inequity and improve safety and quality of genetic healthcare.
{"title":"\"All doctors should be trained in that\": The co-production and mixed-methods evaluation of an educational toolkit to enable safe, high-quality genetic healthcare for people with intellectual disability.","authors":"Iva Strnadová, Manjekah Dunn, Chloe Molnar, Julie Loblinzk, Jackie Leach Scully, Joanne Danker, Michelle Tso, Tiffany Qing Lim, Yasmin Cathcart-King, Karen-Maia Jackaman, Sarah Hayes, Sierra Angelina Willow, Jackie Boyle, Jennifer Hansen, Skie Sarfaraz, Caroline Basckin, Celia Halliburton, Thulasee Sri Ganeshan, Edwina K Middleton, Bronwyn Terrill, Elizabeth Emma Palmer","doi":"10.1016/j.gim.2025.101371","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101371","url":null,"abstract":"<p><strong>Purpose: </strong>People with intellectual disability inequitably access high-quality genetic healthcare. Yet, they are keen to understand more about genetic healthcare and recommend clinicians need education on delivering more inclusive care and that multi-modal genetic health literacy resources should be co-produced.</p><p><strong>Methods: </strong>Our inclusive research team applied best practice co-production principles to deliver a suite of resources, the GeneEQUAL Toolkit. Mixed-methods evaluation including surveys and a focus group/interviews assessed (i) clinicians' perceived capabilities, motivation, and opportunities for providing inclusive healthcare for people with intellectual disability before and after exploring the Toolkit; (ii) the perceptions and opinions of people with intellectual disability about the Toolkit; (iii) the reach of the Toolkit components; and (iv) the reflections of people with intellectual disability and clinicians on the co-production process.</p><p><strong>Results: </strong>The Toolkit met the expectations and preferences of people with intellectual disability and clinicians and had global reach. Co-production was feasible and judged critical for the high value of the Toolkit, in motivating clinicians to change their clinical practice and empowering people with intellectual disability.</p><p><strong>Conclusion: </strong>Co-production can be successfully applied to improve the engagement of people with intellectual disability and potentially reduce health inequity and improve safety and quality of genetic healthcare.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101371"},"PeriodicalIF":6.6,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074451","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}
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