Pub Date : 2025-11-01Epub Date: 2025-09-09DOI: 10.1016/j.gim.2025.101531
Lina Shao, Vimla Aggarwal, Nan Jiang, Sung-Hae L. Kang, Joie Olayiwola, John M. O’Shea, Gordana Raca, Jennifer Sanmann, Elizabeth Spiteri, Fady M. Mikhail, ACMG Laboratory Quality Assurance Committee
This document was reaffirmed by the ACMG Board of Directors as of 23 June 2025 with the following addendum.
截至2025年6月23日，行政协调组董事会重申了该文件，并附上以下增编。
{"title":"Addendum: Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Lina Shao, Vimla Aggarwal, Nan Jiang, Sung-Hae L. Kang, Joie Olayiwola, John M. O’Shea, Gordana Raca, Jennifer Sanmann, Elizabeth Spiteri, Fady M. Mikhail, ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2025.101531","DOIUrl":"10.1016/j.gim.2025.101531","url":null,"abstract":"<div><div>This document was reaffirmed by the ACMG Board of Directors as of 23 June 2025 with the following addendum.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101531"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020723","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 : 2025-11-01Epub Date: 2025-08-19DOI: 10.1016/j.gim.2025.101556
Lu Shi , Katherine Kolor , Zhuo Chen , Christine Y. Lu , Juan Rodriguez , Muin J. Khoury , Scott D. Grosse
Purpose
Recent clinical guidelines have broadened the criteria for BRCA counseling and testing for women and men, including indications based on family history, personal history, and current diagnosis of breast, ovarian, pancreatic, and prostate cancer.
Methods
Using claims data from 2013 to 2022, we identified BRCA testing using procedure codes to evaluate annual utilization, median expenditures per enrollee, and the percentage of 0 out-of-pocket expenditures by sex among enrollees aged 18 to 64 years who were continuously enrolled within calendar years. We examined BRCA utilization by metropolitan status and indications.
Results
Annual BRCA testing utilization among women (and men) increased 10.2% (44.5%) per year during 2014 to 2015 and 1.7% (10.0%) per year during 2016 to 2019, decreased 34.4% (44.8%) in 2020, and rebounded 8.5% (22.3%) per year during 2021 to 2022, remaining below prepandemic levels in 2022. Median expenditures for comprehensive BRCA testing per enrollee decreased by 68% from 2013 to 2022, most of whom had 0 out-of-pocket expenditures. Most BRCA testing was done based on family health history of breast, ovarian, or prostate cancer and among women aged 18 to 50 years.
Conclusion
Health care providers who are knowledgeable about evolving indications for germline BRCA testing can help ensure that eligible individuals have access to germline BRCA testing as preventive service.
{"title":"BRCA genetic testing utilization and expenditures among privately insured adults in the United States, 2013 to 2022","authors":"Lu Shi , Katherine Kolor , Zhuo Chen , Christine Y. Lu , Juan Rodriguez , Muin J. Khoury , Scott D. Grosse","doi":"10.1016/j.gim.2025.101556","DOIUrl":"10.1016/j.gim.2025.101556","url":null,"abstract":"<div><h3>Purpose</h3><div>Recent clinical guidelines have broadened the criteria for BRCA counseling and testing for women and men, including indications based on family history, personal history, and current diagnosis of breast, ovarian, pancreatic, and prostate cancer.</div></div><div><h3>Methods</h3><div>Using claims data from 2013 to 2022, we identified BRCA testing using procedure codes to evaluate annual utilization, median expenditures per enrollee, and the percentage of 0 out-of-pocket expenditures by sex among enrollees aged 18 to 64 years who were continuously enrolled within calendar years. We examined BRCA utilization by metropolitan status and indications.</div></div><div><h3>Results</h3><div>Annual BRCA testing utilization among women (and men) increased 10.2% (44.5%) per year during 2014 to 2015 and 1.7% (10.0%) per year during 2016 to 2019, decreased 34.4% (44.8%) in 2020, and rebounded 8.5% (22.3%) per year during 2021 to 2022, remaining below prepandemic levels in 2022. Median expenditures for comprehensive BRCA testing per enrollee decreased by 68% from 2013 to 2022, most of whom had 0 out-of-pocket expenditures. Most BRCA testing was done based on family health history of breast, ovarian, or prostate cancer and among women aged 18 to 50 years.</div></div><div><h3>Conclusion</h3><div>Health care providers who are knowledgeable about evolving indications for germline BRCA testing can help ensure that eligible individuals have access to germline BRCA testing as preventive service.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101556"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951072","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 : 2025-11-01Epub Date: 2025-08-13DOI: 10.1016/j.gim.2025.101555
Amber S.E. van Oirsouw , Pavla Nedbalova , Miroslava Hancarova , Jan Prchal , Darina Prchalova , Marketa Vlckova , Sarka Bendova , Kristin G. Monaghan , Lisa M. Dyer , Yanmin Chen , Deanna Alexis Carere , Emma A.M. te Bogt , Heather Fisher , Angela E. Scheuerle , Stephanie Riley , Mahim Jain , Weiyi Mu , Joann N. Bodurtha , Albertien M. van Eerde , Marijn F. Stokman , Richard H. van Jaarsveld
Purpose
XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.
Methods
We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning.
Results
A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation.
Conclusion
Our results establish XPO1 as a novel dominant monogenic neurodevelopmental disorder gene and demonstrate a central role for XPO1 in development.
{"title":"Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder","authors":"Amber S.E. van Oirsouw , Pavla Nedbalova , Miroslava Hancarova , Jan Prchal , Darina Prchalova , Marketa Vlckova , Sarka Bendova , Kristin G. Monaghan , Lisa M. Dyer , Yanmin Chen , Deanna Alexis Carere , Emma A.M. te Bogt , Heather Fisher , Angela E. Scheuerle , Stephanie Riley , Mahim Jain , Weiyi Mu , Joann N. Bodurtha , Albertien M. van Eerde , Marijn F. Stokman , Richard H. van Jaarsveld","doi":"10.1016/j.gim.2025.101555","DOIUrl":"10.1016/j.gim.2025.101555","url":null,"abstract":"<div><h3>Purpose</h3><div><em>XPO1</em> functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.</div></div><div><h3>Methods</h3><div>We collected clinical data of individuals with de novo <em>XPO1</em> variants through online matchmaking. We used <em>Drosophila</em> to study <em>XPO1</em> function in development and habituation learning.</div></div><div><h3>Results</h3><div>A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. We demonstrate <em>XPO1</em> functions in development by ubiquitous and neuron-specific knockdown in <em>Drosophila</em>. GABAergic neuron specific knockdown flies demonstrated impaired habituation.</div></div><div><h3>Conclusion</h3><div>Our results establish <em>XPO1</em> as a novel dominant monogenic neurodevelopmental disorder gene and demonstrate a central role for <em>XPO1</em> in development.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101555"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862238","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 : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.gim.2025.101540
Nicola Longo , Takashi Hamazaki , Suzanne Hollander , Anita MacDonald , Ania C. Muntau , Ida Vanessa D. Schwartz
Phenylketonuria (PKU) is an inherited metabolic disorder characterized by the accumulation of toxic phenylalanine levels in the brain that can lead to neurocognitive impairment if untreated. This review evaluates unmet needs in PKU, the importance of newborn screening (NBS), and considerations for chronic treatment options. An international group of experts reviewed the available literature across ethnicities and geographies to identify unmet needs of individuals with PKU. Treatment was assessed in a global context to address patient benefit. Reflecting challenges to the worldwide PKU community, some countries have been unable to implement NBS programs and/or do not apply a treatment-for-life approach. Ongoing challenges for individuals with PKU include maintaining adherence to treatment guidelines for patient- and practice-specific reasons, such as inadequate access to low-cost treatment, insufficient social support, limited clinical staffing, and disease burden. Dietary interventions may not adequately address all symptoms, and some of the current pharmacotherapies may be associated with limited efficacy or adverse events. Several new therapies are being evaluated for the treatment of PKU, offering the potential to address unmet needs. Global availability of NBS programs, access to treatments, and a tenacious commitment to treatment-for-life are expected to improve outcomes for individuals with PKU across geographic regions.
{"title":"Global considerations for lifelong management and therapeutic development for phenylketonuria","authors":"Nicola Longo , Takashi Hamazaki , Suzanne Hollander , Anita MacDonald , Ania C. Muntau , Ida Vanessa D. Schwartz","doi":"10.1016/j.gim.2025.101540","DOIUrl":"10.1016/j.gim.2025.101540","url":null,"abstract":"<div><div>Phenylketonuria (PKU) is an inherited metabolic disorder characterized by the accumulation of toxic phenylalanine levels in the brain that can lead to neurocognitive impairment if untreated. This review evaluates unmet needs in PKU, the importance of newborn screening (NBS), and considerations for chronic treatment options. An international group of experts reviewed the available literature across ethnicities and geographies to identify unmet needs of individuals with PKU. Treatment was assessed in a global context to address patient benefit. Reflecting challenges to the worldwide PKU community, some countries have been unable to implement NBS programs and/or do not apply a treatment-for-life approach. Ongoing challenges for individuals with PKU include maintaining adherence to treatment guidelines for patient- and practice-specific reasons, such as inadequate access to low-cost treatment, insufficient social support, limited clinical staffing, and disease burden. Dietary interventions may not adequately address all symptoms, and some of the current pharmacotherapies may be associated with limited efficacy or adverse events. Several new therapies are being evaluated for the treatment of PKU, offering the potential to address unmet needs. Global availability of NBS programs, access to treatments, and a tenacious commitment to treatment-for-life are expected to improve outcomes for individuals with PKU across geographic regions.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101540"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788887","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 : 2025-11-01Epub Date: 2025-08-23DOI: 10.1016/j.gim.2025.101571
Niina Loponen , Roope A. Kallionpää , Heli Ylä-Outinen , Mikko Valtanen , Kari Auranen , Hannu Järveläinen , Sirkku Peltonen , Juha Peltonen
Purpose
To analyze the risk and prognosis of myocardial infarction in patients with neurofibromatosis type 1 (NF1) in a Finnish population-based cohort from 1987 to 2021.
Methods
A cohort of 1811 individuals with confirmed NF1 was compared with a control cohort of 18,006 individuals who were matched for sex, date of birth, and municipality. Diagnoses of myocardial infarction and potentially associated risk factors were retrieved from the Finnish Care Register for Health Care and the Causes of Death Register over the years 1987 to 2021.
Results
We observed 42 individuals with NF1 (19 women and 23 men) with myocardial infarction. The hazard ratio (HR) for all was 1.36 (95% CI 0.98-1.88); for women 1.58 (95% CI 0.97-2.57), and for men 1.24 (95% CI 0.81-1.91). The diagnoses preceding myocardial infarction in patients with NF1 did not differ from controls. Disease-specific 5-year survival after hospital admission for myocardial infarction was 69.2% (95% CI 54.8-87.6) in patients with NF1 and 85.0% (95% CI 81.0-89.2) in controls, corresponding to a significantly worse prognosis in the NF1 group (HR 2.22, 95% CI 1.16-4.24). NF1-related cancers and sleep apnea often occurred in association with deaths caused by myocardial infarction.
Conclusion
NF1 appears to be frequently associated with myocardial infarction and a subsequent significantly poor survival.
目的：分析1987-2021年芬兰人群队列中1型神经纤维瘤病（NF1）患者心肌梗死的风险和预后。方法：将1811名确诊NF1患者的队列与18006名性别、出生日期和城市相匹配的对照队列进行比较。心肌梗死的诊断和潜在的相关危险因素从1987-2021年的芬兰卫生保健护理登记册和死亡原因登记册中检索。结果：我们观察到42例NF1患者（女性19例，男性23例）合并心肌梗死。所有病例的风险比（HR）为1.36 (95% CI 0.98-1.88)；女性为1.58 (95% CI 0.97-2.57)，男性为1.24 （95% CI 0.81-1.91）。NF1患者心肌梗死前的诊断与对照组没有差异。NF1组因心肌梗死入院后的疾病特异性5年生存率为69.2% (95% CI 54.8-87.6)，对照组为85.0% (95% CI 81.0-89.2)， NF1组的预后明显较差（HR 2.22, 95% CI 1.16-4.24）。nf1相关的癌症和睡眠呼吸暂停常与心肌梗死引起的死亡有关。结论：NF1似乎经常与心肌梗死和随后的显着低生存率相关。
{"title":"Risk and prognosis of myocardial infarction in patients with neurofibromatosis type 1: Evidence of compromised survival","authors":"Niina Loponen , Roope A. Kallionpää , Heli Ylä-Outinen , Mikko Valtanen , Kari Auranen , Hannu Järveläinen , Sirkku Peltonen , Juha Peltonen","doi":"10.1016/j.gim.2025.101571","DOIUrl":"10.1016/j.gim.2025.101571","url":null,"abstract":"<div><h3>Purpose</h3><div>To analyze the risk and prognosis of myocardial infarction in patients with neurofibromatosis type 1 (NF1) in a Finnish population-based cohort from 1987 to 2021.</div></div><div><h3>Methods</h3><div>A cohort of 1811 individuals with confirmed NF1 was compared with a control cohort of 18,006 individuals who were matched for sex, date of birth, and municipality. Diagnoses of myocardial infarction and potentially associated risk factors were retrieved from the Finnish Care Register for Health Care and the Causes of Death Register over the years 1987 to 2021.</div></div><div><h3>Results</h3><div>We observed 42 individuals with NF1 (19 women and 23 men) with myocardial infarction. The hazard ratio (HR) for all was 1.36 (95% CI 0.98-1.88); for women 1.58 (95% CI 0.97-2.57), and for men 1.24 (95% CI 0.81-1.91). The diagnoses preceding myocardial infarction in patients with NF1 did not differ from controls. Disease-specific 5-year survival after hospital admission for myocardial infarction was 69.2% (95% CI 54.8-87.6) in patients with NF1 and 85.0% (95% CI 81.0-89.2) in controls, corresponding to a significantly worse prognosis in the NF1 group (HR 2.22, 95% CI 1.16-4.24). NF1-related cancers and sleep apnea often occurred in association with deaths caused by myocardial infarction.</div></div><div><h3>Conclusion</h3><div>NF1 appears to be frequently associated with myocardial infarction and a subsequent significantly poor survival.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101571"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951406","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 : 2025-11-01Epub Date: 2025-08-27DOI: 10.1016/j.gim.2025.101573
Subash Thapa , Mette Just Bonde , Anja Leppin
Purpose
To systematically review the implementation strategies, outcomes, and quality of interventions aimed at increasing the uptake of breast cancer-related genetic testing services among women who are at high-risk.
Methods
A systematic search was conducted on PubMed, CINAHL, PsycINFO, EMBASE, Cochrane Library, and Campbell Coordinating Group databases from January 2005 to October 2024. Studies were included if they evaluated interventions to increase genetic testing uptake or facilitate decision making about genetic testing.
Results
A total of 27 articles were identified, including 18 interventions aimed at supporting the uptake of genetic testing for breast cancer. Half of the interventions evaluated face-to-face counseling, whereas the other half used alternative counseling modalities, such as standardized DVD counseling, tailored written materials, and remote video or telephone counseling. Participant satisfaction was consistently high (≥80%) among most interventions; however, cost analyses suggested time savings with alternative delivery strategies. Nevertheless, feasibility varied according to the delivery mode. Remote video counseling faced some technical challenges, decision aids/patient education materials were partly less engaging, and alternative counseling modalities might provide more limited opportunities to discuss emotional and social concerns. None of the interventions progressed beyond early adoption.
Conclusion
Alternative approaches to genetic counseling, such as video- and telephone-based delivery and tailored written materials, show promise in terms of feasibility and acceptability. Future research should adopt more rigorous, framework-guided implementation methods with attention to long-term sustainability, while also promoting greater consistency in terminology to improve transparency and comparability.
{"title":"Implementing interventions to increase genetic testing for breast cancer among high-risk populations: A systematic review of implementation strategies, outcomes, and gaps","authors":"Subash Thapa , Mette Just Bonde , Anja Leppin","doi":"10.1016/j.gim.2025.101573","DOIUrl":"10.1016/j.gim.2025.101573","url":null,"abstract":"<div><h3>Purpose</h3><div>To systematically review the implementation strategies, outcomes, and quality of interventions aimed at increasing the uptake of breast cancer-related genetic testing services among women who are at high-risk.</div></div><div><h3>Methods</h3><div>A systematic search was conducted on PubMed, CINAHL, PsycINFO, EMBASE, Cochrane Library, and Campbell Coordinating Group databases from January 2005 to October 2024. Studies were included if they evaluated interventions to increase genetic testing uptake or facilitate decision making about genetic testing.</div></div><div><h3>Results</h3><div>A total of 27 articles were identified, including 18 interventions aimed at supporting the uptake of genetic testing for breast cancer. Half of the interventions evaluated face-to-face counseling, whereas the other half used alternative counseling modalities, such as standardized DVD counseling, tailored written materials, and remote video or telephone counseling. Participant satisfaction was consistently high (≥80%) among most interventions; however, cost analyses suggested time savings with alternative delivery strategies. Nevertheless, feasibility varied according to the delivery mode. Remote video counseling faced some technical challenges, decision aids/patient education materials were partly less engaging, and alternative counseling modalities might provide more limited opportunities to discuss emotional and social concerns. None of the interventions progressed beyond early adoption.</div></div><div><h3>Conclusion</h3><div>Alternative approaches to genetic counseling, such as video- and telephone-based delivery and tailored written materials, show promise in terms of feasibility and acceptability. Future research should adopt more rigorous, framework-guided implementation methods with attention to long-term sustainability, while also promoting greater consistency in terminology to improve transparency and comparability.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101573"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951114","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 : 2025-11-01Epub Date: 2025-09-04DOI: 10.1016/j.gim.2025.101565
Sophie Allen , Charlie F. Rowlands , Samantha Butler , Miranda Durkie , Carrie Horton , Tina Pesaran , Marcy Richardson , Rachel Robinson , Alice Garrett , George J. Burghel , Alison Callaway , Joanne Field , Bethan Frugtniet , Sheila Palmer-Smith , Jonathan Grant , Judith Pagan , Trudi McDevitt , Katie Snape , Avgi Andreou , Eamonn R. Maher , Z. Kemp
Purpose
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH.
Methods
We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of “very-rare” variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework.
Results
For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 “hotspot” regions wherein the DS-VRMV-LR increased to 1226.9.
Conclusion
These data provide quantitative measures for very rare missense and truncating variants in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.
{"title":"Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer","authors":"Sophie Allen , Charlie F. Rowlands , Samantha Butler , Miranda Durkie , Carrie Horton , Tina Pesaran , Marcy Richardson , Rachel Robinson , Alice Garrett , George J. Burghel , Alison Callaway , Joanne Field , Bethan Frugtniet , Sheila Palmer-Smith , Jonathan Grant , Judith Pagan , Trudi McDevitt , Katie Snape , Avgi Andreou , Eamonn R. Maher , Z. Kemp","doi":"10.1016/j.gim.2025.101565","DOIUrl":"10.1016/j.gim.2025.101565","url":null,"abstract":"<div><h3>Purpose</h3><div>Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in <em>FH</em> (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in <em>FH.</em></div></div><div><h3>Methods</h3><div>We collated clinical diagnostic testing data on germline <em>FH</em> variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of “very-rare” variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log<sub>2.08</sub> likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework.</div></div><div><h3>Results</h3><div>For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 “hotspot” regions wherein the DS-VRMV-LR increased to 1226.9.</div></div><div><h3>Conclusion</h3><div>These data provide quantitative measures for very rare missense and truncating variants in <em>FH</em>, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101565"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015074","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 : 2025-11-01Epub Date: 2025-09-06DOI: 10.1016/j.gim.2025.101574
Georgia Pitsava , Megan Hawley , Light Auriga , Ivan de Dios , Arthur Ko , Sofia Marmolejos , Miguel Almalvez , Ingrid Chen , Kaylee Scozzaro , Jianhua Zhao , Rebekah Barrick , Nicholas Ah Mew , Vincent A. Fusaro , Jonathan LoTempio , Matthew Taylor , Luisa Mestroni , Sharon Graw , Dianna Milewicz , Dongchuan Guo , David R. Murdock , Eric Vilain
Purpose
Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.
Methods
We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.
Results
We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis.
Conclusion
Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.
{"title":"Genome sequencing reveals the impact of pseudoexons in rare genetic disease","authors":"Georgia Pitsava , Megan Hawley , Light Auriga , Ivan de Dios , Arthur Ko , Sofia Marmolejos , Miguel Almalvez , Ingrid Chen , Kaylee Scozzaro , Jianhua Zhao , Rebekah Barrick , Nicholas Ah Mew , Vincent A. Fusaro , Jonathan LoTempio , Matthew Taylor , Luisa Mestroni , Sharon Graw , Dianna Milewicz , Dongchuan Guo , David R. Murdock , Eric Vilain","doi":"10.1016/j.gim.2025.101574","DOIUrl":"10.1016/j.gim.2025.101574","url":null,"abstract":"<div><h3>Purpose</h3><div>Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.</div></div><div><h3>Methods</h3><div>We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.</div></div><div><h3>Results</h3><div>We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis.</div></div><div><h3>Conclusion</h3><div>Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101574"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029420","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 : 2025-11-01Epub Date: 2025-08-23DOI: 10.1016/j.gim.2025.101568
Morgan Ehman , Kartik Sharma , Deirdre Weymann , Tatiana Maroilley , Arezoo Mohajeri , Anna Lehman , Maja Tarailo-Graovac , Steven J.M. Jones , Marco A. Marra , Wyeth W. Wasserman , Nadine R. Caron , Laura Arbour , Dean A. Regier
Purpose
Indigenous peoples are underrepresented in reference genome libraries. Consequently, rare disease diagnosis may require bespoke bioinformatics analyses of genome sequences. Establishing diagnostic cost is crucial to support policy development for equitable diagnosis of rare diseases. We estimated the cost and cost trajectory of diagnostic genome sequencing and bioinformatics for Indigenous participants with suspected rare diseases.
Methods
We conducted a microcosting study of Indigenous children and their families receiving genome sequencing through Canada’s Silent Genomes Project. Invoice data informed the costs of genome sequencing. We conducted a time-and-motion study for bioinformatics analyses, including labor, computing, and data storage costs.
Results
With standard bioinformatics, costs ranged from C$3645 (SD: 455) for singletons to C$7402 (SD: 566) for trios. With advanced, bespoke bioinformatics, costs ranged from C$5344 (SD: 634) for singletons to C$9760 (SD: 822) for trios. Genome sequencing was a primary cost driver; however, sequencing costs decreased by 61% over 4 years. Bioinformatics costs ranged from 21.3% to 58.3% of the total costs. The time required for bioinformatics ranged from 71 hours to 215 hours for standard and advanced analyses, respectively.
Conclusion
Genome sequencing costs decreased over time. Bioinformatics is a significant cost driver, particularly for bespoke analyses arising from nonrepresentative reference libraries.
{"title":"The cost and cost trajectory of genome sequencing and bioinformatics analysis for Indigenous children with suspected rare diseases","authors":"Morgan Ehman , Kartik Sharma , Deirdre Weymann , Tatiana Maroilley , Arezoo Mohajeri , Anna Lehman , Maja Tarailo-Graovac , Steven J.M. Jones , Marco A. Marra , Wyeth W. Wasserman , Nadine R. Caron , Laura Arbour , Dean A. Regier","doi":"10.1016/j.gim.2025.101568","DOIUrl":"10.1016/j.gim.2025.101568","url":null,"abstract":"<div><h3>Purpose</h3><div>Indigenous peoples are underrepresented in reference genome libraries. Consequently, rare disease diagnosis may require bespoke bioinformatics analyses of genome sequences. Establishing diagnostic cost is crucial to support policy development for equitable diagnosis of rare diseases. We estimated the cost and cost trajectory of diagnostic genome sequencing and bioinformatics for Indigenous participants with suspected rare diseases.</div></div><div><h3>Methods</h3><div>We conducted a microcosting study of Indigenous children and their families receiving genome sequencing through Canada’s Silent Genomes Project. Invoice data informed the costs of genome sequencing. We conducted a time-and-motion study for bioinformatics analyses, including labor, computing, and data storage costs.</div></div><div><h3>Results</h3><div>With standard bioinformatics, costs ranged from C$3645 (SD: 455) for singletons to C$7402 (SD: 566) for trios. With advanced, bespoke bioinformatics, costs ranged from C$5344 (SD: 634) for singletons to C$9760 (SD: 822) for trios. Genome sequencing was a primary cost driver; however, sequencing costs decreased by 61% over 4 years. Bioinformatics costs ranged from 21.3% to 58.3% of the total costs. The time required for bioinformatics ranged from 71 hours to 215 hours for standard and advanced analyses, respectively.</div></div><div><h3>Conclusion</h3><div>Genome sequencing costs decreased over time. Bioinformatics is a significant cost driver, particularly for bespoke analyses arising from nonrepresentative reference libraries.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101568"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951395","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 : 2025-11-01Epub Date: 2025-08-13DOI: 10.1016/j.gim.2025.101554
Alissa M. D’Gama , Jessica Douglas , Sonia Hills , Monica H. Wojcik , Casie A. Genetti , Aubrie Soucy Verran
Purpose
Through our implementation study providing rapid genomic sequencing (rGS) in safety-net neonatal intensive care units (NICUs), we investigated the feasibility and perceived usefulness of customized “clinical interpretive reports” (CIRs) to help neonatal providers with interpreting, disclosing, and managing care based on rGS results.
Methods
Enrolled infants received rGS through a clinically accredited vendor. We developed 5 CIR types to provide customized interpretation of rGS results and link results to clinical management considerations, research opportunities, and resources. We developed workflows to triage, create, and deliver CIRs within 3 business days. Providers received the vendor reports and CIRs, disclosed results, and completed post-disclosure surveys. We analyzed summary statistics for the first 100 cases.
Results
We delivered 97 of 100 CIRs (97%) within our goal time frame (average 1.3 days) and provided clinical management recommendations in 40 of 100 (40%). Neonatal providers completed the post-disclosure surveys for 86 of 100 disclosures (86%). Most reported using the CIR before disclosure (80/86, 93%) and found it helpful at providing useful information beyond the vendor report (79/80, 99%).
Conclusion
It is feasible and useful to develop customized rGS reports to assist non-genetics providers in safety-net NICU settings. Similar approaches may hold promise for equitably advancing genomic care in non-NICU settings.
{"title":"Implementing customized genomic sequencing reports to empower providers in safety-net neonatal intensive care units","authors":"Alissa M. D’Gama , Jessica Douglas , Sonia Hills , Monica H. Wojcik , Casie A. Genetti , Aubrie Soucy Verran","doi":"10.1016/j.gim.2025.101554","DOIUrl":"10.1016/j.gim.2025.101554","url":null,"abstract":"<div><h3>Purpose</h3><div>Through our implementation study providing rapid genomic sequencing (rGS) in safety-net neonatal intensive care units (NICUs), we investigated the feasibility and perceived usefulness of customized “clinical interpretive reports” (CIRs) to help neonatal providers with interpreting, disclosing, and managing care based on rGS results.</div></div><div><h3>Methods</h3><div>Enrolled infants received rGS through a clinically accredited vendor. We developed 5 CIR types to provide customized interpretation of rGS results and link results to clinical management considerations, research opportunities, and resources. We developed workflows to triage, create, and deliver CIRs within 3 business days. Providers received the vendor reports and CIRs, disclosed results, and completed post-disclosure surveys. We analyzed summary statistics for the first 100 cases.</div></div><div><h3>Results</h3><div>We delivered 97 of 100 CIRs (97%) within our goal time frame (average 1.3 days) and provided clinical management recommendations in 40 of 100 (40%). Neonatal providers completed the post-disclosure surveys for 86 of 100 disclosures (86%). Most reported using the CIR before disclosure (80/86, 93%) and found it helpful at providing useful information beyond the vendor report (79/80, 99%).</div></div><div><h3>Conclusion</h3><div>It is feasible and useful to develop customized rGS reports to assist non-genetics providers in safety-net NICU settings. Similar approaches may hold promise for equitably advancing genomic care in non-NICU settings.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101554"},"PeriodicalIF":6.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859102","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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