Pub Date : 2025-10-10DOI: 10.1016/j.gim.2025.101604
Ibrahim T. Khoja , Dawn S. Peck , Dimitar K. Gavrilov , Molly A. McPheron , Devin Oglesbee , Gisele Bentz Pino , Katie L. Sapp , Matthew J. Schultz , April L. Studinski Jones , Amy L. White , Silvia Tortorelli , Dietrich Matern , Patricia L. Hall
Purpose
To review the performance and outcomes of a second-tier newborn screening test for Pompe disease.
Methods
We followed our previously published screening approach that reduces false-positive results by incorporating creatine and creatinine levels and postanalytic tools in a second-tier test.
Results
We reviewed 1879 blood samples from neonates born in 11 states. Second-tier testing effectively reduced false-positive results, compared with first-tier enzyme testing alone. Only a small number of screen-positive cases (n = 7) were confirmed to have infantile-onset Pompe disease. No false-negative cases of infantile-onset Pompe disease were identified in this cohort, and 6 cases of possible late-onset Pompe disease were not detected with this approach.
Conclusion
This tiered screening strategy discriminated well between true- and false-positive results and improved the positive predictive value. However, it did not reliably differentiate between infantile- and late-onset Pompe disease.
{"title":"Reduction of false-positive results with biochemical second-tier testing for newborn screening of Pompe disease","authors":"Ibrahim T. Khoja , Dawn S. Peck , Dimitar K. Gavrilov , Molly A. McPheron , Devin Oglesbee , Gisele Bentz Pino , Katie L. Sapp , Matthew J. Schultz , April L. Studinski Jones , Amy L. White , Silvia Tortorelli , Dietrich Matern , Patricia L. Hall","doi":"10.1016/j.gim.2025.101604","DOIUrl":"10.1016/j.gim.2025.101604","url":null,"abstract":"<div><h3>Purpose</h3><div>To review the performance and outcomes of a second-tier newborn screening test for Pompe disease.</div></div><div><h3>Methods</h3><div>We followed our previously published screening approach that reduces false-positive results by incorporating creatine and creatinine levels and postanalytic tools in a second-tier test.</div></div><div><h3>Results</h3><div>We reviewed 1879 blood samples from neonates born in 11 states. Second-tier testing effectively reduced false-positive results, compared with first-tier enzyme testing alone. Only a small number of screen-positive cases (<em>n</em> = 7) were confirmed to have infantile-onset Pompe disease. No false-negative cases of infantile-onset Pompe disease were identified in this cohort, and 6 cases of possible late-onset Pompe disease were not detected with this approach.</div></div><div><h3>Conclusion</h3><div>This tiered screening strategy discriminated well between true- and false-positive results and improved the positive predictive value. However, it did not reliably differentiate between infantile- and late-onset Pompe disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101604"},"PeriodicalIF":6.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285945","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 : 2025-10-10DOI: 10.1016/j.gim.2025.101603
Jincong Q. Freeman , Yijia Sun , Wenji Guo , Briseis Aschebrook-Kilfoy , Cara Essling , Jan-Marie McEvilly , Ilona Siljander , Hatice Basdag , Olufunmilayo I. Olopade , Dezheng Huo
Purpose
To examine awareness, knowledge, and attitudes toward breast cancer (BC) polygenic risk scores (PRS) in women with high risk.
Methods
We surveyed women without BC enrolled in the Chicago Multiethnic Epidemiologic BC Cohort and Cancer Prone Registry between July and September 2024. PRS awareness was defined as having ever read/heard about PRS and discussed PRS with a provider. PRS knowledge scores range from 0 to 11. Higher scores indicate better knowledge. We also asked to what extent participants agreed that PRS testing should be offered to the general population or a routine part of BC risk assessment and how likely receiving PRS would influence their risk management behaviors.
Results
Of 828 women, 18.5% had read/heard about PRS, and 13.2% discussed PRS with a provider. Non-Hispanic White women scored slightly higher on PRS knowledge than Non-Hispanic Black and multiracial/other women. Higher education (P-trend < .001) and income (P-trend = .002) levels were associated with increased knowledge scores. More than 90.0% agreed/strongly agreed that PRS testing should be offered to the general population or a routine part of risk assessment. In total, 94.0% reported that PRS receipt would likely/very likely influence their risk management behaviors.
Conclusion
This study suggests an opportunity for tailored PRS education interventions and the need to improve patient-provider communication and knowledge gaps when implementing genetic testing to increase personalized BC screening.
{"title":"Awareness, knowledge, and attitudes toward polygenic risk scores for breast cancer in multiethnic high-risk cohorts of women","authors":"Jincong Q. Freeman , Yijia Sun , Wenji Guo , Briseis Aschebrook-Kilfoy , Cara Essling , Jan-Marie McEvilly , Ilona Siljander , Hatice Basdag , Olufunmilayo I. Olopade , Dezheng Huo","doi":"10.1016/j.gim.2025.101603","DOIUrl":"10.1016/j.gim.2025.101603","url":null,"abstract":"<div><h3>Purpose</h3><div>To examine awareness, knowledge, and attitudes toward breast cancer (BC) polygenic risk scores (PRS) in women with high risk.</div></div><div><h3>Methods</h3><div>We surveyed women without BC enrolled in the Chicago Multiethnic Epidemiologic BC Cohort and Cancer Prone Registry between July and September 2024. PRS awareness was defined as having ever read/heard about PRS and discussed PRS with a provider. PRS knowledge scores range from 0 to 11. Higher scores indicate better knowledge. We also asked to what extent participants agreed that PRS testing should be offered to the general population or a routine part of BC risk assessment and how likely receiving PRS would influence their risk management behaviors.</div></div><div><h3>Results</h3><div>Of 828 women, 18.5% had read/heard about PRS, and 13.2% discussed PRS with a provider. Non-Hispanic White women scored slightly higher on PRS knowledge than Non-Hispanic Black and multiracial/other women. Higher education (<em>P</em>-trend < .001) and income (<em>P</em>-trend = .002) levels were associated with increased knowledge scores. More than 90.0% agreed/strongly agreed that PRS testing should be offered to the general population or a routine part of risk assessment. In total, 94.0% reported that PRS receipt would likely/very likely influence their risk management behaviors.</div></div><div><h3>Conclusion</h3><div>This study suggests an opportunity for tailored PRS education interventions and the need to improve patient-provider communication and knowledge gaps when implementing genetic testing to increase personalized BC screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101603"},"PeriodicalIF":6.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286016","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 : 2025-10-10DOI: 10.1016/j.gim.2025.101598
Anne B. Arnett , Ryan Koesterer , Paulina Gonzalez Tovar , Mia O’Connell , Soleha Patel , Han Zhang , Courtney E. French , Shira Rockowitz , Jason Flannick , Ryan Doan
Purpose
Pediatric attention deficit hyperactivity disorder (ADHD, OMIM 143465) is highly heritable, yet the genetic architecture of the condition remains poorly understood. This study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.
Methods
Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across 5 methods, including 2 published genome-wide association studies and 2 publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established American College of Medical Genetics and Genomics variant interpretation guidelines.
Results
ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ polygenic scores, ancestry, and rare variant status with 70% area under the curve.
Conclusion
The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome-wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.
{"title":"Common and rare genetic variants explain distinct diagnostic variance in pediatric attention deficit hyperactivity disorder","authors":"Anne B. Arnett , Ryan Koesterer , Paulina Gonzalez Tovar , Mia O’Connell , Soleha Patel , Han Zhang , Courtney E. French , Shira Rockowitz , Jason Flannick , Ryan Doan","doi":"10.1016/j.gim.2025.101598","DOIUrl":"10.1016/j.gim.2025.101598","url":null,"abstract":"<div><h3>Purpose</h3><div>Pediatric attention deficit hyperactivity disorder (ADHD, OMIM <span><span>143465</span><svg><path></path></svg></span>) is highly heritable, yet the genetic architecture of the condition remains poorly understood. This study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.</div></div><div><h3>Methods</h3><div>Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across 5 methods, including 2 published genome-wide association studies and 2 publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established American College of Medical Genetics and Genomics variant interpretation guidelines.</div></div><div><h3>Results</h3><div>ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ polygenic scores, ancestry, and rare variant status with 70% area under the curve.</div></div><div><h3>Conclusion</h3><div>The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome-wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101598"},"PeriodicalIF":6.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274466","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 : 2025-10-07DOI: 10.1016/j.gim.2025.101557
Joanne Ngeow , Jianbang Chiang , Esteban Astiazaran-Symonds , Judith Balmaña , Ilana Cass , Felix K.F. Kommoss , William D. Foulkes , Paul A. James , Arielle Katcher , Susan Klugman , Alicia A. Livinski , Julie S. Mak , Nicoleta Voian , Myra J. Wick , Marc Tischkowitz , Tuya Pal , Douglas R. Stewart , Helen Hanson , ACMG Professional Practice and Guidelines Committee
Purpose
RAD51C, RAD51D, and BRIP1 germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing RAD51C, RAD51D, and BRIP1 heterozygotes in clinical practice are limited.
Methods
An international workgroup developed a Clinical Practice Resource to guide management of RAD51C, RAD51D, and BRIP1 heterozygotes using peer-reviewed publications and expert opinion.
Results
RAD51C, RAD51D, and BRIP1 are moderate (intermediate) penetrance ovarian cancer predisposition genes. Ovarian cancer risks for individuals with RAD51C, RAD51D, and BRIP1 GPVs may be influenced by family history and other modifiers. RAD51C and RAD51D GPVs are also associated with moderate risk of breast cancer, predominantly triple-negative subtype. RAD51C, RAD51D, and BRIP1 heterozygotes should be offered risk-reducing salpingo-oophorectomy close to the age of menopause based on age-specific risks and shared decision making. For RAD51C and RAD51D heterozygotes, enhanced breast surveillance may be indicated according to their personalized risk estimate and country-specific guidelines. Generally, risk-reducing mastectomy is not recommended. For RAD51C, RAD51D, and BRIP1 heterozygotes who develop cancer, there is insufficient evidence to guide any specific targeted treatment.
Conclusion
Systematic prospective data collection is needed to establish the outcomes of RAD51C, RAD51D, and BRIP1 associated cancers and particularly response to cancer treatment and survival.
{"title":"Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)","authors":"Joanne Ngeow , Jianbang Chiang , Esteban Astiazaran-Symonds , Judith Balmaña , Ilana Cass , Felix K.F. Kommoss , William D. Foulkes , Paul A. James , Arielle Katcher , Susan Klugman , Alicia A. Livinski , Julie S. Mak , Nicoleta Voian , Myra J. Wick , Marc Tischkowitz , Tuya Pal , Douglas R. Stewart , Helen Hanson , ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2025.101557","DOIUrl":"10.1016/j.gim.2025.101557","url":null,"abstract":"<div><h3>Purpose</h3><div><em>RAD51C, RAD51D,</em> and <em>BRIP1</em> germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes in clinical practice are limited.</div></div><div><h3>Methods</h3><div>An international workgroup developed a Clinical Practice Resource to guide management of <em>RAD51C</em>, <em>RAD51D,</em> and <em>BRIP1</em> heterozygotes using peer-reviewed publications and expert opinion.</div></div><div><h3>Results</h3><div><em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> are moderate (intermediate) penetrance ovarian cancer predisposition genes. Ovarian cancer risks for individuals with <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> GPVs may be influenced by family history and other modifiers. <em>RAD51C</em> and <em>RAD51D</em> GPVs are also associated with moderate risk of breast cancer, predominantly triple-negative subtype. <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes should be offered risk-reducing salpingo-oophorectomy close to the age of menopause based on age-specific risks and shared decision making. For <em>RAD51C</em> and <em>RAD51D</em> heterozygotes, enhanced breast surveillance may be indicated according to their personalized risk estimate and country-specific guidelines. Generally, risk-reducing mastectomy is not recommended. For <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> heterozygotes who develop cancer, there is insufficient evidence to guide any specific targeted treatment.</div></div><div><h3>Conclusion</h3><div>Systematic prospective data collection is needed to establish the outcomes of <em>RAD51C</em>, <em>RAD51D</em>, and <em>BRIP1</em> associated cancers and particularly response to cancer treatment and survival.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101557"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266880","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 : 2025-10-01DOI: 10.1016/j.gim.2025.101595
Katharina Valentin , Monika Kustermann , Mona R. Schneider , Haleh Aminfar , Kathrin Vollnhofer , Andreas Wedrich , Christoph Stapf , Martin Bertich , Markus Ritter , Theresa Mendrina , Daniel Valcanover , Walter Berger , Margret Eckhard , Andy Sombke , Stephanie V. Lilja , Amina Paquay , Bernhard Rosensteiner , Iris Schmidt , Reginald E. Bittner , Thomas P. Georgi , Wolfgang M. Schmidt
Purpose
Hereditary optic atrophy (OA) represents one of the leading causes of blindness. A relatively large number of genes, many of which are implicated in mitochondrial function, are known to be involved in OA. For many affected individuals, however, a genetic cause still cannot be identified.
Methods
In a large pedigree and additional families, exome sequencing was used to identify a genetic cause in individuals with so far genetically unresolved OA. Subsequently, mitochondrial function was studied in cultured dermal fibroblasts.
Results
Exome sequencing revealed a heterozygous missense variant in PPIB [NM_000942.5:c.538C>T p.(Arg180Trp)], encoding peptidylprolyl isomerase B, which segregated with clinically isolated OA in 19 individuals from 9 families. PPIB-associated OA involves an insidious reduction in visual acuity, central scotoma, and inner retinal layer thinning consistent with other autosomal dominant OAs. Age of symptom onset was mostly in adulthood (median: 36 years), and severity of clinical manifestation was variable. Patient-derived fibroblasts revealed altered mitochondrial morphology, as well as subtle respiratory chain defects.
Conclusion
The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. Although future studies are needed to study the exact pathomechanistic role of PPIB, insights from this work broaden the knowledge of genes implicated in autosomal dominant OA.
{"title":"A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy","authors":"Katharina Valentin , Monika Kustermann , Mona R. Schneider , Haleh Aminfar , Kathrin Vollnhofer , Andreas Wedrich , Christoph Stapf , Martin Bertich , Markus Ritter , Theresa Mendrina , Daniel Valcanover , Walter Berger , Margret Eckhard , Andy Sombke , Stephanie V. Lilja , Amina Paquay , Bernhard Rosensteiner , Iris Schmidt , Reginald E. Bittner , Thomas P. Georgi , Wolfgang M. Schmidt","doi":"10.1016/j.gim.2025.101595","DOIUrl":"10.1016/j.gim.2025.101595","url":null,"abstract":"<div><h3>Purpose</h3><div>Hereditary optic atrophy (OA) represents one of the leading causes of blindness. A relatively large number of genes, many of which are implicated in mitochondrial function, are known to be involved in OA. For many affected individuals, however, a genetic cause still cannot be identified.</div></div><div><h3>Methods</h3><div>In a large pedigree and additional families, exome sequencing was used to identify a genetic cause in individuals with so far genetically unresolved OA. Subsequently, mitochondrial function was studied in cultured dermal fibroblasts.</div></div><div><h3>Results</h3><div>Exome sequencing revealed a heterozygous missense variant in <em>PPIB</em> [NM_000942.5:c.538C>T p.(Arg180Trp)], encoding peptidylprolyl isomerase B, which segregated with clinically isolated OA in 19 individuals from 9 families. <em>PPIB</em>-associated OA involves an insidious reduction in visual acuity, central scotoma, and inner retinal layer thinning consistent with other autosomal dominant OAs. Age of symptom onset was mostly in adulthood (median: 36 years), and severity of clinical manifestation was variable. Patient-derived fibroblasts revealed altered mitochondrial morphology, as well as subtle respiratory chain defects.</div></div><div><h3>Conclusion</h3><div>The <em>PPIB</em> variant segregates with OA, which might be caused by compromised mitochondrial function. Although future studies are needed to study the exact pathomechanistic role of <em>PPIB</em>, insights from this work broaden the knowledge of genes implicated in autosomal dominant OA.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101595"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225233","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 : 2025-10-01Epub Date: 2025-07-07DOI: 10.1016/j.gim.2025.101521
Erja Nynäs, Sonja Sulkava, Anna K Nurmi, Maija Suvanto, Kristiina Aittomäki, Heli Nevanlinna
Purpose: Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking.
Methods: We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals.
Results: Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 × 10-6) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 × 10-7), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA.
Conclusion: Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.
目的：杂合子FANCM变异与乳腺癌（BC）有关。只有少数研究调查了其他类型的癌症。在病例报告中，双等位基因截断变异与范可尼贫血（FA）样癌症易感综合征有关，但缺乏癌症的范围和风险估计。方法：我们研究了芬兰富集变异c.5101C >0tp .（Gln1701Ter）和c.5791C >tp .（Arg1931Ter）与FinnGen数据中500,348人患任何癌症和fa相关疾病风险的关系。结果：杂合子c.5101C>T （N=10,940）与BC风险增加相关（OR = 1.24, P = 2.7×10-6），但也与包括下咽癌在内的其他癌症类型的风险相关（OR = 3.98, P = 3.6×10-7），表明风险效应比先前描述的更广泛。纯合子c.5101C>T （N=76）与乳腺癌、头颈部、胃肠道、妇科、血液学、皮肤和肺癌的高风险相关，而c.5791C>T则罕见。此外，癌症治疗后发现卵巢功能障碍和血液学副作用的高隐性风险，但没有骨髓衰竭或FA的物理特征的风险。结论：基于与双等位基因变异相关的风险模式，我们提出了一种不同于FA和其他特征性癌症易感综合征的新型FANCM癌症综合征。
{"title":"Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure.","authors":"Erja Nynäs, Sonja Sulkava, Anna K Nurmi, Maija Suvanto, Kristiina Aittomäki, Heli Nevanlinna","doi":"10.1016/j.gim.2025.101521","DOIUrl":"10.1016/j.gim.2025.101521","url":null,"abstract":"<p><strong>Purpose: </strong>Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking.</p><p><strong>Methods: </strong>We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals.</p><p><strong>Results: </strong>Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 × 10<sup>-6</sup>) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 × 10<sup>-7</sup>), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA.</p><p><strong>Conclusion: </strong>Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101521"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608224","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 : 2025-10-01DOI: 10.1016/j.gim.2025.101594
Alexander Bernier , Bartha Maria Knoppers , Jonathan Lawson , Robyn McDougall , Maili Raven-Adams , Vasiliki Rahimzadeh
Purpose
Standardizing contractual clauses that govern data access enables research institutions to responsibly steward genomic and related health data while enabling its efficient downstream reuse.
Methods
We describe a document analysis study using both qualitative and comparative law analytical approaches to identify the most common categories of clauses from 29 different data access agreements used by human biomedical research consortia globally. We furthermore characterized the legal positions and standard practices for each common element of the agreement and synthesized across them to develop model clauses. A total of 3 discussion sessions were organized virtually to refine the clauses among members of the Ethical Provenance Subgroup of the Global Alliance for Genomics and Health.
Results
We developed 15 unique data access clauses corresponding to the most common legal elements identified in the sampled agreements.
Conclusion
Model clauses can be used to drive administrative efficiencies and institutional compliance for managing access to human genomic data for research. Additional machine-readable consents and software solutions are needed to support traceable “ethical provenance” of human genomic data and communicate data use conditions throughout the data’s life-cycle.
{"title":"Toward ethical provenance tracking: The GA4GH model data access agreement (DAA)","authors":"Alexander Bernier , Bartha Maria Knoppers , Jonathan Lawson , Robyn McDougall , Maili Raven-Adams , Vasiliki Rahimzadeh","doi":"10.1016/j.gim.2025.101594","DOIUrl":"10.1016/j.gim.2025.101594","url":null,"abstract":"<div><h3>Purpose</h3><div>Standardizing contractual clauses that govern data access enables research institutions to responsibly steward genomic and related health data while enabling its efficient downstream reuse.</div></div><div><h3>Methods</h3><div>We describe a document analysis study using both qualitative and comparative law analytical approaches to identify the most common categories of clauses from 29 different data access agreements used by human biomedical research consortia globally. We furthermore characterized the legal positions and standard practices for each common element of the agreement and synthesized across them to develop model clauses. A total of 3 discussion sessions were organized virtually to refine the clauses among members of the Ethical Provenance Subgroup of the Global Alliance for Genomics and Health.</div></div><div><h3>Results</h3><div>We developed 15 unique data access clauses corresponding to the most common legal elements identified in the sampled agreements.</div></div><div><h3>Conclusion</h3><div>Model clauses can be used to drive administrative efficiencies and institutional compliance for managing access to human genomic data for research. Additional machine-readable consents and software solutions are needed to support traceable “ethical provenance” of human genomic data and communicate data use conditions throughout the data’s life-cycle.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101594"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232428","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 : 2025-09-30DOI: 10.1016/j.gim.2025.101593
Runjun D. Kumar, Sarah A. Paolucci, Brittany Williams, Daniel W. Serber, Claire L. Wittowski, Ankita Jhuraney, Dru F. Leistritz, Jillian G. Buchan
Purpose
Clinical testing of rare genetic variants relies on population genomic data sets as a source of evidence. New data sets from the Genome Aggregation Database and All of Us Research Program are many-fold larger than previous data sets, and the latter includes highly detailed phenotype data. The effect of these data sets on variant classification and reporting for highly penetrant pediatric-onset disease is not well characterized; however, one likely effect is reduced reporting of variants of uncertain significance (VUS).
Methods
We retrospectively identified VUS previously reported by our clinically licensed laboratory and evaluated whether they are still reportable based on new reference data sets.
Results
By examining allele counts in new data sets, we identified 24 variants that are likely no longer reportable. Additionally, the All of Us phenotype data suggest that an additional 10 VUS are no longer reportable. Overall, we found that nearly one-fifth of VUS (34/173, 19.6%) are no longer reportable.
Conclusion
We conclude that the use of these new data sets is likely to reduce reported VUS for highly penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of All of Us phenotype data.
{"title":"Real-world effects of using gnomAD 4.1.0 and All of Us population reference data sets on reporting of variants of uncertain significance","authors":"Runjun D. Kumar, Sarah A. Paolucci, Brittany Williams, Daniel W. Serber, Claire L. Wittowski, Ankita Jhuraney, Dru F. Leistritz, Jillian G. Buchan","doi":"10.1016/j.gim.2025.101593","DOIUrl":"10.1016/j.gim.2025.101593","url":null,"abstract":"<div><h3>Purpose</h3><div>Clinical testing of rare genetic variants relies on population genomic data sets as a source of evidence. New data sets from the Genome Aggregation Database and All of Us Research Program are many-fold larger than previous data sets, and the latter includes highly detailed phenotype data. The effect of these data sets on variant classification and reporting for highly penetrant pediatric-onset disease is not well characterized; however, one likely effect is reduced reporting of variants of uncertain significance (VUS).</div></div><div><h3>Methods</h3><div>We retrospectively identified VUS previously reported by our clinically licensed laboratory and evaluated whether they are still reportable based on new reference data sets.</div></div><div><h3>Results</h3><div>By examining allele counts in new data sets, we identified 24 variants that are likely no longer reportable. Additionally, the All of Us phenotype data suggest that an additional 10 VUS are no longer reportable. Overall, we found that nearly one-fifth of VUS (34/173, 19.6%) are no longer reportable.</div></div><div><h3>Conclusion</h3><div>We conclude that the use of these new data sets is likely to reduce reported VUS for highly penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of All of Us phenotype data.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101593"},"PeriodicalIF":6.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212300","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 : 2025-09-30DOI: 10.1016/j.gim.2025.101596
Kaili Yin , Qingwei Qi , Xiya Zhou , Na Hao , Ru Wang , Jiazhen Chang , Mengmeng Li , Xueting Yang , Mingming Wang , Yan Lü , Yulin Jiang
Purpose
Secondary findings (SFs) identified through genomic sequencing are results unrelated to the primary indication but with potential clinical utility. Although genomic technologies are increasingly used in perinatal diagnosis, the clinical implications of SFs remain insufficiently explored. We evaluated the detection rates, phenotypic concordance, and clinical implications of SFs in a prenatal cohort undergoing trio exome sequencing (trio-ES).
Methods
This was a single-center cohort study of 424 consecutive families who underwent prenatal trio-ES at a tertiary maternal-fetal medicine center from January 2019 to December 2023. SFs were classified using a 3-category framework (medically actionable risks, childhood-onset diseases, and carrier status) and analyzed via a stepwise protocol, including validation by a specialized clinical review panel.
Results
Among 1272 individuals, SFs were identified in 2.9% (37/1272), including 2.1% of fetuses (9/424) and 3.3% of parents (28/848). SF-related phenotypes were observed in 1 fetus and 3 adults. SFs prompted medical management changes in 27.0% (10/37) of cases, including 1 pregnancy termination, 7 adults initiating medical evaluations, and 2 couples committing to prenatal diagnosis/neonatal screening in subsequent pregnancies.
Conclusion
Systematic SF reporting in prenatal diagnosis has demonstrated clinical value by facilitating pregnancy decisions, informing parental health risks, and enabling preventive reproductive strategies.
{"title":"The clinical utility of systematic reporting of secondary findings in prenatal diagnosis","authors":"Kaili Yin , Qingwei Qi , Xiya Zhou , Na Hao , Ru Wang , Jiazhen Chang , Mengmeng Li , Xueting Yang , Mingming Wang , Yan Lü , Yulin Jiang","doi":"10.1016/j.gim.2025.101596","DOIUrl":"10.1016/j.gim.2025.101596","url":null,"abstract":"<div><h3>Purpose</h3><div>Secondary findings (SFs) identified through genomic sequencing are results unrelated to the primary indication but with potential clinical utility. Although genomic technologies are increasingly used in perinatal diagnosis, the clinical implications of SFs remain insufficiently explored. We evaluated the detection rates, phenotypic concordance, and clinical implications of SFs in a prenatal cohort undergoing trio exome sequencing (trio-ES).</div></div><div><h3>Methods</h3><div>This was a single-center cohort study of 424 consecutive families who underwent prenatal trio-ES at a tertiary maternal-fetal medicine center from January 2019 to December 2023. SFs were classified using a 3-category framework (medically actionable risks, childhood-onset diseases, and carrier status) and analyzed via a stepwise protocol, including validation by a specialized clinical review panel.</div></div><div><h3>Results</h3><div>Among 1272 individuals, SFs were identified in 2.9% (37/1272), including 2.1% of fetuses (9/424) and 3.3% of parents (28/848). SF-related phenotypes were observed in 1 fetus and 3 adults. SFs prompted medical management changes in 27.0% (10/37) of cases, including 1 pregnancy termination, 7 adults initiating medical evaluations, and 2 couples committing to prenatal diagnosis/neonatal screening in subsequent pregnancies.</div></div><div><h3>Conclusion</h3><div>Systematic SF reporting in prenatal diagnosis has demonstrated clinical value by facilitating pregnancy decisions, informing parental health risks, and enabling preventive reproductive strategies.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101596"},"PeriodicalIF":6.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225335","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 : 2025-09-29DOI: 10.1016/j.gim.2025.101592
Annelieke R. Müller , Bibiche den Hollander , Agnies M. van Eeghen , Peter M. van de Ven , Martina Cornel , Mieke van Haelst , Jan J. Sprengers , Hilgo Bruining , Marion M. Brands , Clara D. van Karnebeek
Treatments often do not reach individuals affected with a rare disease because of several barriers. Legislation generally requires that therapies for rare diseases are tested and licensed according to the same rules as established for common diseases. However, conventional methods for evaluating treatment effectiveness are hampered by the small patient populations. Single-case experimental designs (SCEDs), including n-of-1 trials, may offer a solution. Advantages of SCEDs include the ability to study individualized treatment options, use of within-participant randomization to generate a high level of evidence, and guarantee that each individual receives treatment. Their individualized approach also has a positive impact on ensuring relevance of treatment approaches and outcomes for affected individuals. However, designing and performing SCEDs in rare diseases comes with specific challenges related to heterogeneity, selection of outcome measures, accessibility of therapy, development of study medication, treatment and trial adherence, regulation, reimbursement, and financial limitations. Here, the lessons learned from SCEDs in rare diseases are discussed, based on real-world experiences from the involved clinicians and researchers, and informal participants’ comments collected during and after participation in a SCED. Following these experiences and a thorough evaluation by an expert group, a manual for conducting SCEDs has been developed. This manual is presented as a steppingstone toward robust evidence generation and better access to treatments for individuals with rare diseases.
{"title":"Overcoming treatment implementation barriers for individuals with rare diseases using single-case experimental designs","authors":"Annelieke R. Müller , Bibiche den Hollander , Agnies M. van Eeghen , Peter M. van de Ven , Martina Cornel , Mieke van Haelst , Jan J. Sprengers , Hilgo Bruining , Marion M. Brands , Clara D. van Karnebeek","doi":"10.1016/j.gim.2025.101592","DOIUrl":"10.1016/j.gim.2025.101592","url":null,"abstract":"<div><div>Treatments often do not reach individuals affected with a rare disease because of several barriers. Legislation generally requires that therapies for rare diseases are tested and licensed according to the same rules as established for common diseases. However, conventional methods for evaluating treatment effectiveness are hampered by the small patient populations. Single-case experimental designs (SCEDs), including n-of-1 trials, may offer a solution. Advantages of SCEDs include the ability to study individualized treatment options, use of within-participant randomization to generate a high level of evidence, and guarantee that each individual receives treatment. Their individualized approach also has a positive impact on ensuring relevance of treatment approaches and outcomes for affected individuals. However, designing and performing SCEDs in rare diseases comes with specific challenges related to heterogeneity, selection of outcome measures, accessibility of therapy, development of study medication, treatment and trial adherence, regulation, reimbursement, and financial limitations. Here, the lessons learned from SCEDs in rare diseases are discussed, based on real-world experiences from the involved clinicians and researchers, and informal participants’ comments collected during and after participation in a SCED. Following these experiences and a thorough evaluation by an expert group, a manual for conducting SCEDs has been developed. This manual is presented as a steppingstone toward robust evidence generation and better access to treatments for individuals with rare diseases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101592"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206302","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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