Pub Date : 2025-10-21DOI: 10.1016/j.gim.2025.101614
Steven Pastor , Oanh Tran , Ryan Lapointe , Arnold Z. Olali , Douglas C. Wallace , Bernice Morrow , Elaine H. Zackai , Donna M. McDonald-McGinn , Beverly S. Emanuel
Purpose
The genomic architecture of 22q11.2 deletion syndrome (22q11.2DS) has primarily been studied in White populations, despite evidence suggesting a lower prevalence in Black individuals. This study aims to improve our understanding of the population-specific organization of 22q11.2 genomic structures.
Methods
Optical mapping data from 106 genomes, representing various Black and White individuals, were analyzed to assess the structure and variation of the 22q11.2 low copy repeats (LCR22s).
Results
Extensive variability in copy-number and orientation of LCR22 elements was observed between Black and White genomes. Several novel copy-number variants and haplotype configurations were identified, some being private or more prevalent within specific groups. Notably, copy-number variants diversity was particularly striking among Black genomes. Comparisons of Black and White families with de novo 22q11.2DS probands revealed unique nonallelic homologous recombination scenarios, with Black families exhibiting recombination patterns that are not previously observed.
Conclusion
Perhaps the unique and highly variable LCR22 haplotype configurations in Black individuals contribute to the lower observed prevalence of 22q11.2DS by inhibiting the likelihood of nonallelic homologous recombination, the mechanism that leads to the syndrome.
{"title":"Optical mapping in Black genomes: Distinct LCR22 structures and 22q11.2 deletion syndrome mechanisms","authors":"Steven Pastor , Oanh Tran , Ryan Lapointe , Arnold Z. Olali , Douglas C. Wallace , Bernice Morrow , Elaine H. Zackai , Donna M. McDonald-McGinn , Beverly S. Emanuel","doi":"10.1016/j.gim.2025.101614","DOIUrl":"10.1016/j.gim.2025.101614","url":null,"abstract":"<div><h3>Purpose</h3><div>The genomic architecture of 22q11.2 deletion syndrome (22q11.2DS) has primarily been studied in White populations, despite evidence suggesting a lower prevalence in Black individuals. This study aims to improve our understanding of the population-specific organization of 22q11.2 genomic structures.</div></div><div><h3>Methods</h3><div>Optical mapping data from 106 genomes, representing various Black and White individuals, were analyzed to assess the structure and variation of the 22q11.2 low copy repeats (LCR22s).</div></div><div><h3>Results</h3><div>Extensive variability in copy-number and orientation of LCR22 elements was observed between Black and White genomes. Several novel copy-number variants and haplotype configurations were identified, some being private or more prevalent within specific groups. Notably, copy-number variants diversity was particularly striking among Black genomes. Comparisons of Black and White families with de novo 22q11.2DS probands revealed unique nonallelic homologous recombination scenarios, with Black families exhibiting recombination patterns that are not previously observed.</div></div><div><h3>Conclusion</h3><div>Perhaps the unique and highly variable LCR22 haplotype configurations in Black individuals contribute to the lower observed prevalence of 22q11.2DS by inhibiting the likelihood of nonallelic homologous recombination, the mechanism that leads to the syndrome.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101614"},"PeriodicalIF":6.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367879","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 : 2025-10-15DOI: 10.1016/j.gim.2025.101615
Cynthia J. Tifft , Isabela Batsu , Roberto Giugliani , Harmonie Goyeau , Andreas Hahn , Simon A. Jones , Pascal Minini , Ichiro Nakashima , Mar O’Callaghan , Susan Perlman , Nathan Thibault , Madhurima Uppara Kowthalam , Riliang Zheng , Timothy M. Cox
Purpose
To evaluate efficacy and safety of venglustat for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) and cognate diseases.
Methods
The AMETHIST phase 3, randomized, double-blind, placebo-controlled study evaluated oral venglustat (N = 40) vs placebo (N = 19) in adults with late-onset GM2 gangliosidoses. Coprimary endpoints were annual percent change on the 9-Hole Peg Test and percent change in cerebrospinal fluid (CSF) GM2 ganglioside from baseline to week 104. A secondary population of participants with cognate diseases (N = 16) received open-label venglustat in a “basket” trial.
Results
CSF GM2 decreased by 47.6% (90% CI: −52.6, −42.6) with venglustat versus 11.3% (90% CI: −18.3, −4.4) with placebo (difference: −36.2 [90% CI: −44.8, −27.7], P < .0001). The annual percent change in 9-Hole Peg Test was 2.49% (90% CI: 0.28, 4.74) with venglustat versus 0.95% (90% CI: −2.16, 4.15) with placebo (difference: 1.54% [90% CI: −2.33, 5.39], P = .74). Decreased CSF GM2 concentrations did not correlate with clinical endpoints. Secondary population participants remained clinically stable. The most common adverse events were fall, headache, and contusion with placebo and fall, and COVID-19 and headache with venglustat.
Conclusion
In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed.
{"title":"Venglustat in GM2 gangliosidoses and related disorders: Results of the AMETHIST randomized controlled and basket trials","authors":"Cynthia J. Tifft , Isabela Batsu , Roberto Giugliani , Harmonie Goyeau , Andreas Hahn , Simon A. Jones , Pascal Minini , Ichiro Nakashima , Mar O’Callaghan , Susan Perlman , Nathan Thibault , Madhurima Uppara Kowthalam , Riliang Zheng , Timothy M. Cox","doi":"10.1016/j.gim.2025.101615","DOIUrl":"10.1016/j.gim.2025.101615","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate efficacy and safety of venglustat for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) and cognate diseases.</div></div><div><h3>Methods</h3><div>The AMETHIST phase 3, randomized, double-blind, placebo-controlled study evaluated oral venglustat (<em>N</em> = 40) vs placebo (<em>N</em> = 19) in adults with late-onset GM2 gangliosidoses. Coprimary endpoints were annual percent change on the 9-Hole Peg Test and percent change in cerebrospinal fluid (CSF) GM2 ganglioside from baseline to week 104. A secondary population of participants with cognate diseases (<em>N</em> = 16) received open-label venglustat in a “basket” trial.</div></div><div><h3>Results</h3><div>CSF GM2 decreased by 47.6% (90% CI: −52.6, −42.6) with venglustat versus 11.3% (90% CI: −18.3, −4.4) with placebo (difference: −36.2 [90% CI: −44.8, −27.7], <em>P</em> < .0001). The annual percent change in 9-Hole Peg Test was 2.49% (90% CI: 0.28, 4.74) with venglustat versus 0.95% (90% CI: −2.16, 4.15) with placebo (difference: 1.54% [90% CI: −2.33, 5.39], <em>P</em> = .74). Decreased CSF GM2 concentrations did not correlate with clinical endpoints. Secondary population participants remained clinically stable. The most common adverse events were fall, headache, and contusion with placebo and fall, and COVID-19 and headache with venglustat.</div></div><div><h3>Conclusion</h3><div>In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101615"},"PeriodicalIF":6.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312759","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 : 2025-10-14DOI: 10.1016/j.gim.2025.101599
Chloe Mighton, Emma Reble, Jordan Sam, Rita Kodida, Salma Shickh, Marc Clausen, Daena Hirjikaka, Sonya Grewal, Seema Panchal, Carolyn Piccinin, Melyssa Aronson, Thomas Ward, Susan Randall Armel, Larissa Peck, Tracy Graham, Yael Silberman, Nicole Forster, José-Mario Capo-Chichi, Elena Greenfeld, Abdul Noor, Iris Cohn, Chantal F Morel, Christine Elser, Andrea Eisen, Emily Glogowksi, Kasmintan A Schrader, Raymond H Kim, Kelvin K W Chan, Kevin E Thorpe, Jordan Lerner-Ellis, Yvonne Bombard
Purpose: Exome and genome sequencing enable opportunistic screening for secondary findings (SFs). We report on exome analysis for a broad range of medically relevant SFs in the setting of the Incidental Genomics randomized clinical trial (NCT03597165).
Methods: Participants had exome sequencing and were randomized to receive only primary cancer findings (control), or cancer findings and a choice of SFs (intervention).
Results: Across 279 participants, there were 4441 unique variants in SF genes: 5.0% (221) were reportable pathogenic (P)/likely pathogenic (LP) variants, and 81.4% (3615) were non-reportable variants of uncertain significance (VUS). Intervention arm participants had on average 2.6 (SD 1.66, range 0-9) P/LP variants and 29.5 VUS (SD 13.2, range 2-74). SFs for monogenic disease risk were reported in 35.3% (49/139) of participants (ACMG subset in 1.4%), and carrier status in 89.3% (117/131). In the intervention arm, variant filtration was 7.7 times longer per case (95% CI 5.3 to 11.3, p<0.0001) and variant classification was 13.3 times longer (95% CI 10.6 to 16.5, p<0.0001), and report preparation 3.3 times longer (95% CI 2.6 to 4.1, p<0.0001).
Conclusions: While the yield of reportable SFs was high, this was accompanied by many non-reportable VUS and increased efforts for exome analysis.
目的：外显子组和基因组测序使继发性发现（sf）的机会筛选成为可能。我们报道了在偶然基因组随机临床试验（NCT03597165）中广泛的医学相关SFs的外显子组分析。方法：参与者进行了外显子组测序，并被随机分为仅接受原发性癌症发现（对照组）或癌症发现和sf选择（干预）。结果：279名参与者中，SF基因有4441个独特变异：5.0%（221个）是可报告的致病(P)/可能致病（LP）变异，81.4%（3615个）是不确定意义（VUS）的不可报告变异。干预组参与者平均有2.6个（SD 1.66，范围0-9）P/LP变异和29.5个VUS （SD 13.2，范围2-74）。35.3%（49/139）的参与者报告了单基因疾病风险的sf (ACMG亚群为1.4%),89.3%（117/131）的参与者报告了携带者状态。在干预组中，每个病例的变异过滤时间为7.7倍（95% CI 5.3至11.3）。结论：虽然可报告的SFs的产量很高，但这伴随着许多不可报告的VUS，并且增加了外显子组分析的工作量。
{"title":"Opportunistic screening for broad range of medically relevant secondary findings: Laboratory benefits and burdens.","authors":"Chloe Mighton, Emma Reble, Jordan Sam, Rita Kodida, Salma Shickh, Marc Clausen, Daena Hirjikaka, Sonya Grewal, Seema Panchal, Carolyn Piccinin, Melyssa Aronson, Thomas Ward, Susan Randall Armel, Larissa Peck, Tracy Graham, Yael Silberman, Nicole Forster, José-Mario Capo-Chichi, Elena Greenfeld, Abdul Noor, Iris Cohn, Chantal F Morel, Christine Elser, Andrea Eisen, Emily Glogowksi, Kasmintan A Schrader, Raymond H Kim, Kelvin K W Chan, Kevin E Thorpe, Jordan Lerner-Ellis, Yvonne Bombard","doi":"10.1016/j.gim.2025.101599","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101599","url":null,"abstract":"<p><strong>Purpose: </strong>Exome and genome sequencing enable opportunistic screening for secondary findings (SFs). We report on exome analysis for a broad range of medically relevant SFs in the setting of the Incidental Genomics randomized clinical trial (NCT03597165).</p><p><strong>Methods: </strong>Participants had exome sequencing and were randomized to receive only primary cancer findings (control), or cancer findings and a choice of SFs (intervention).</p><p><strong>Results: </strong>Across 279 participants, there were 4441 unique variants in SF genes: 5.0% (221) were reportable pathogenic (P)/likely pathogenic (LP) variants, and 81.4% (3615) were non-reportable variants of uncertain significance (VUS). Intervention arm participants had on average 2.6 (SD 1.66, range 0-9) P/LP variants and 29.5 VUS (SD 13.2, range 2-74). SFs for monogenic disease risk were reported in 35.3% (49/139) of participants (ACMG subset in 1.4%), and carrier status in 89.3% (117/131). In the intervention arm, variant filtration was 7.7 times longer per case (95% CI 5.3 to 11.3, p<0.0001) and variant classification was 13.3 times longer (95% CI 10.6 to 16.5, p<0.0001), and report preparation 3.3 times longer (95% CI 2.6 to 4.1, p<0.0001).</p><p><strong>Conclusions: </strong>While the yield of reportable SFs was high, this was accompanied by many non-reportable VUS and increased efforts for exome analysis.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101599"},"PeriodicalIF":6.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307527","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 : 2025-10-14DOI: 10.1016/j.gim.2025.101613
Vanessa C. Jacovas , Michelle Zelnick , Shannon McNulty , Justyne E. Ross , Namrata Khurana , Xueyang Pan , Alejandro Nieto , Shiloh Martin , Benjamin McLean , Marwa A. Elnagheeb , Morton J. Cowan , Jennifer M. Puck , Mike S. Hershfield , James Verbsky , Jolan Walter , Eric J. Allenspach , Alice Y. Chan , Nicolai S.C. van Oers , Rajarshi Ghosh , Megan Piazza , Xinrui Shi
Purpose
This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2.
Methods
The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants.
Results
Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance, 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes.
Conclusion
The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.
{"title":"The ClinGen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications for classification of variants in ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2","authors":"Vanessa C. Jacovas , Michelle Zelnick , Shannon McNulty , Justyne E. Ross , Namrata Khurana , Xueyang Pan , Alejandro Nieto , Shiloh Martin , Benjamin McLean , Marwa A. Elnagheeb , Morton J. Cowan , Jennifer M. Puck , Mike S. Hershfield , James Verbsky , Jolan Walter , Eric J. Allenspach , Alice Y. Chan , Nicolai S.C. van Oers , Rajarshi Ghosh , Megan Piazza , Xinrui Shi","doi":"10.1016/j.gim.2025.101613","DOIUrl":"10.1016/j.gim.2025.101613","url":null,"abstract":"<div><h3>Purpose</h3><div>This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: <em>ADA</em>, <em>DCLRE1C</em>, <em>IL2RG</em>, <em>IL7R</em>, <em>JAK3</em>, <em>RAG1</em>, and <em>RAG2</em>.</div></div><div><h3>Methods</h3><div>The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants.</div></div><div><h3>Results</h3><div>Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance, 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes.</div></div><div><h3>Conclusion</h3><div>The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101613"},"PeriodicalIF":6.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307533","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 : 2025-10-11DOI: 10.1016/j.gim.2025.101597
David Cheerie , Marlen C. Lauffer , Logan Newton , Kimberly Amburgey , Danique Beijer , Bushra Haque , Brian T. Kalish , Margaret M. Meserve , Rachel Y. Oh , Amy Y. Pan , Miriam S. Reuter , Michael J. Szego , Anna Szuto
Purpose
To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.
Methods
We retrospectively applied the N=1 Collaborative’s Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different ASO approaches, or “unable to assess.”
Results
In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.
Conclusion
A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.
{"title":"Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study","authors":"David Cheerie , Marlen C. Lauffer , Logan Newton , Kimberly Amburgey , Danique Beijer , Bushra Haque , Brian T. Kalish , Margaret M. Meserve , Rachel Y. Oh , Amy Y. Pan , Miriam S. Reuter , Michael J. Szego , Anna Szuto","doi":"10.1016/j.gim.2025.101597","DOIUrl":"10.1016/j.gim.2025.101597","url":null,"abstract":"<div><h3>Purpose</h3><div>To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.</div></div><div><h3>Methods</h3><div>We retrospectively applied the N=1 Collaborative’s Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different ASO approaches, or “unable to assess.”</div></div><div><h3>Results</h3><div>In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.</div></div><div><h3>Conclusion</h3><div>A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101597"},"PeriodicalIF":6.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291915","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.2025.101605
Robin Z. Hayeems , Wendy J. Ungar , Christian R. Marshall , Meredith K. Gillespie , Anna Szuto , Lijia Huang , Viji Venkataramanan , Bowen Xiao , Caitlin Chisholm , D. James Stavropoulos , Mélanie Beaulieu Bergeron , Whiwon Lee , Gregory Costain , Rebekah Jobling , Sarah Sawyer , E. Magda Price , Lynette Lau , Roberto Mendoza , Martin J. Somerville , Kym M. Boycott
Purpose
Exome sequencing (ES) and genome sequencing (GS) can improve rare disease diagnosis but are not routinely available in many jurisdictions. To inform implementation, we report on a randomized implementation effectiveness trial comparing ES and GS.
Methods
Eligible trios were randomized to receive ES or GS in the same clinically accredited laboratory. Patient-level data on diagnostic utility and turnaround times were collected. Outcomes were compared statistically between clinically important subgroups.
Results
Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (95.5%), and of these, 91.6% included chromosome microarray. Diagnostic yields were 33.8% and 33.6%, for ES (n = 526) and GS (n = 522), respectively. Within sequencing groups, diagnostic results were more frequent among those with ID/DD than those without (P < .005). For routine (ie, nonexpedited) patients (n = 1020), 87.0% were reported in <12 weeks, and the mean turnaround time was 55.5 days (SD: 24.0). Turnaround time for ES and GS did not differ; however, result type (P < .001) and age of onset (P < .005) significantly affected turnaround time.
Conclusion
Findings provide robust evidence of diagnostic utility and timeliness of ES and GS and will inform policy related to the organization, delivery, and reimbursement of clinical-grade genome diagnostics for rare diseases.
{"title":"Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial","authors":"Robin Z. Hayeems , Wendy J. Ungar , Christian R. Marshall , Meredith K. Gillespie , Anna Szuto , Lijia Huang , Viji Venkataramanan , Bowen Xiao , Caitlin Chisholm , D. James Stavropoulos , Mélanie Beaulieu Bergeron , Whiwon Lee , Gregory Costain , Rebekah Jobling , Sarah Sawyer , E. Magda Price , Lynette Lau , Roberto Mendoza , Martin J. Somerville , Kym M. Boycott","doi":"10.1016/j.gim.2025.101605","DOIUrl":"10.1016/j.gim.2025.101605","url":null,"abstract":"<div><h3>Purpose</h3><div>Exome sequencing (ES) and genome sequencing (GS) can improve rare disease diagnosis but are not routinely available in many jurisdictions. To inform implementation, we report on a randomized implementation effectiveness trial comparing ES and GS.</div></div><div><h3>Methods</h3><div>Eligible trios were randomized to receive ES or GS in the same clinically accredited laboratory. Patient-level data on diagnostic utility and turnaround times were collected. Outcomes were compared statistically between clinically important subgroups.</div></div><div><h3>Results</h3><div>Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (95.5%), and of these, 91.6% included chromosome microarray. Diagnostic yields were 33.8% and 33.6%, for ES (<em>n</em> = 526) and GS (<em>n</em> = 522), respectively. Within sequencing groups, diagnostic results were more frequent among those with ID/DD than those without (<em>P</em> < .005). For routine (ie, nonexpedited) patients (<em>n</em> = 1020), 87.0% were reported in <12 weeks, and the mean turnaround time was 55.5 days (SD: 24.0). Turnaround time for ES and GS did not differ; however, result type (<em>P</em> < .001) and age of onset (<em>P</em> < .005) significantly affected turnaround time.</div></div><div><h3>Conclusion</h3><div>Findings provide robust evidence of diagnostic utility and timeliness of ES and GS and will inform policy related to the organization, delivery, and reimbursement of clinical-grade genome diagnostics for rare diseases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101605"},"PeriodicalIF":6.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286002","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.2025.101604
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}
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