Pub Date : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.gim.2025.101623
Maria Stamou , Miranda Tompkins , Hannah Bow , Jessica Kearney , Maleeha Akram , Harrison Brand , Xuefang Zhao , Shadi Zaheri , Neoklis A. Georgopoulos , Odelia Chorin , Yulia Khavkin , Tal Kedar , Margaret F. Lippincott , Lacey Plummer , Michael Talkowski , Yiping Shen , Doris K. Wu , Ravikumar Balasubramanian , Susan Wray , Stephanie B. Seminara
Purpose
The genetic etiology of infertility remains unknown. To identify genes for human infertility, we applied a de novo variant analysis in 142 parent-proband trios with idiopathic hypogonadotropic hypogonadism (IHH), an infertility disorder caused by gonadotropin-releasing hormone (GnRH) deficiency.
Methods
Rare de novo copy-number and single-nucleotide variants (CNVs and SNVs) were called from exome sequencing data of the IHH trios. An association study of common EMX2 variants and disease outcomes was performed in the Massachusetts General Brigham Biobank (N = 65,253). GnRH neuronal development and migration was studied in organotypic explants with knocked down of Emx2 and in a mouse model lacking Emx2.
Results
We identified that the gene EMX2 harbored both rare de novo CNVs and SNVs. Rare de novo EMX2 variants led to IHH, developmental delay, and hearing loss. Common EMX2 variants were linked to infertility, Parkinson disease, and hearing loss. Knockdown of Emx2 in nasal explants resulted in attenuated GnRH cell migration and GnRH cells were confined to nasal regions of Emx2 knockout (KO) mice, consistent with IHH pathogenesis.
Conclusion
By utilizing a de novo variant analysis and cellular assays, EMX2 was uncovered as a gene for human infertility.
{"title":"De novo rare EMX2 variants lead to idiopathic hypogonadotropic hypogonadism","authors":"Maria Stamou , Miranda Tompkins , Hannah Bow , Jessica Kearney , Maleeha Akram , Harrison Brand , Xuefang Zhao , Shadi Zaheri , Neoklis A. Georgopoulos , Odelia Chorin , Yulia Khavkin , Tal Kedar , Margaret F. Lippincott , Lacey Plummer , Michael Talkowski , Yiping Shen , Doris K. Wu , Ravikumar Balasubramanian , Susan Wray , Stephanie B. Seminara","doi":"10.1016/j.gim.2025.101623","DOIUrl":"10.1016/j.gim.2025.101623","url":null,"abstract":"<div><h3>Purpose</h3><div>The genetic etiology of infertility remains unknown. To identify genes for human infertility, we applied a de novo variant analysis in 142 parent-proband trios with idiopathic hypogonadotropic hypogonadism (IHH), an infertility disorder caused by gonadotropin-releasing hormone (GnRH) deficiency.</div></div><div><h3>Methods</h3><div>Rare de novo copy-number and single-nucleotide variants (CNVs and SNVs) were called from exome sequencing data of the IHH trios. An association study of common <em>EMX2</em> variants and disease outcomes was performed in the Massachusetts General Brigham Biobank (<em>N</em> = 65,253). GnRH neuronal development and migration was studied in organotypic explants with knocked down of <em>Emx2</em> and in a mouse model lacking <em>Emx2</em>.</div></div><div><h3>Results</h3><div>We identified that the gene <em>EMX2</em> harbored both rare de novo CNVs and SNVs. Rare de novo <em>EMX2</em> variants led to IHH, developmental delay, and hearing loss. Common <em>EMX2</em> variants were linked to infertility, Parkinson disease, and hearing loss. Knockdown of <em>Emx2</em> in nasal explants resulted in attenuated GnRH cell migration and GnRH cells were confined to nasal regions of <em>Emx2</em> knockout (KO) mice, consistent with IHH pathogenesis.</div></div><div><h3>Conclusion</h3><div>By utilizing a de novo variant analysis and cellular assays, <em>EMX2</em> was uncovered as a gene for human infertility.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101623"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620928","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 : 2026-01-01Epub 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":"2026-01-01","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 : 2026-01-01Epub Date: 2026-01-06DOI: 10.1016/j.gim.2025.101637
Seth I. Berger , Georgia Pitsava , Changrui Xiao , Emmanuèle C. Délot , Eric Vilain
{"title":"Response to Spurdle et al","authors":"Seth I. Berger , Georgia Pitsava , Changrui Xiao , Emmanuèle C. Délot , Eric Vilain","doi":"10.1016/j.gim.2025.101637","DOIUrl":"10.1016/j.gim.2025.101637","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101637"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933048","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 : 2026-01-01Epub 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":"2026-01-01","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 : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.gim.2025.101622
Matthieu Prudhomme , Boris Chaumette , Philippe Nubukpo , Catherine Yardin , Benjamin Laplace
Purpose
Advances in genetic applications within psychiatry offer promising benefits in diagnosis, treatment personalization, and risk prediction. However, ethical concerns—such as fear of discrimination and eugenics—and limited awareness hinder their widespread adoption. This review aims to evaluate the attitudes of psychiatric patients and their relatives toward genetics in psychiatry and to identify the key factors that influence these perceptions.
Methods
A systematic review and meta-analysis adhering to PRISMA guidelines was performed across databases including PubMed, Scopus, and CINAHL up to February 2024. Studies exploring attitudes toward genetics in psychiatry among patients and relatives were included; their quality was assessed using the Quality Assessment Tool for Diverse Studies tool. A qualitative meta-synthesis identified themes, whereas a meta-analysis estimated favorable attitudes.
Results
Seventy studies examined applications such as predictive testing, pharmacogenetics, and genetic counseling. Overall, 80% (95% CI = 0.72 to 0.87) expressed favorable attitudes toward genetic testing. Notable barriers included concerns about discrimination, limited knowledge, and ethical issues related to prenatal testing. Although genetic counseling was positively received, its use remained limited due to lack of awareness.
Conclusion
Despite the promise genetics holds for psychiatry, addressing technical, ethical, and educational challenges is essential for wider acceptance. Future research should focus on underserved populations and prioritize enhancing genetic counseling and professional education to support the responsible integration of genetic advancements.
目的在精神病学中遗传学应用的进展为诊断、治疗个性化和风险预测提供了有希望的益处。然而，伦理问题——比如对歧视和优生学的恐惧——以及有限的意识阻碍了它们的广泛采用。本综述旨在评估精神病患者及其亲属对精神病学遗传学的态度，并确定影响这些看法的关键因素。方法根据PRISMA指南对PubMed、Scopus和CINAHL等数据库进行系统评价和荟萃分析，截止到2024年2月。包括患者及其亲属对精神病学遗传学态度的研究；使用多样化研究质量评估工具对其质量进行评估。定性综合确定主题，而元分析估计有利态度。结果70项研究检查了预测测试、药物遗传学和遗传咨询等应用。总体而言，80% （95% CI = 0.72至0.87）的人对基因检测持赞成态度。值得注意的障碍包括对歧视的担忧，有限的知识，以及与产前检测有关的道德问题。虽然遗传咨询得到了积极的接受，但由于缺乏认识，它的使用仍然有限。尽管遗传学为精神病学带来了希望，但解决技术、伦理和教育方面的挑战对于更广泛的接受是必不可少的。未来的研究应侧重于服务不足的人群，并优先加强遗传咨询和专业教育，以支持遗传进步的负责任整合。
{"title":"Perceptions, knowledge, and attitudes toward genetics among psychiatric patients and their relatives: A systematic review and a meta-analysis","authors":"Matthieu Prudhomme , Boris Chaumette , Philippe Nubukpo , Catherine Yardin , Benjamin Laplace","doi":"10.1016/j.gim.2025.101622","DOIUrl":"10.1016/j.gim.2025.101622","url":null,"abstract":"<div><h3>Purpose</h3><div>Advances in genetic applications within psychiatry offer promising benefits in diagnosis, treatment personalization, and risk prediction. However, ethical concerns—such as fear of discrimination and eugenics—and limited awareness hinder their widespread adoption. This review aims to evaluate the attitudes of psychiatric patients and their relatives toward genetics in psychiatry and to identify the key factors that influence these perceptions.</div></div><div><h3>Methods</h3><div>A systematic review and meta-analysis adhering to PRISMA guidelines was performed across databases including PubMed, Scopus, and CINAHL up to February 2024. Studies exploring attitudes toward genetics in psychiatry among patients and relatives were included; their quality was assessed using the Quality Assessment Tool for Diverse Studies tool. A qualitative meta-synthesis identified themes, whereas a meta-analysis estimated favorable attitudes.</div></div><div><h3>Results</h3><div>Seventy studies examined applications such as predictive testing, pharmacogenetics, and genetic counseling. Overall, 80% (95% CI = 0.72 to 0.87) expressed favorable attitudes toward genetic testing. Notable barriers included concerns about discrimination, limited knowledge, and ethical issues related to prenatal testing. Although genetic counseling was positively received, its use remained limited due to lack of awareness.</div></div><div><h3>Conclusion</h3><div>Despite the promise genetics holds for psychiatry, addressing technical, ethical, and educational challenges is essential for wider acceptance. Future research should focus on underserved populations and prioritize enhancing genetic counseling and professional education to support the responsible integration of genetic advancements.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101622"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620929","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 : 2026-01-01Epub Date: 2025-10-29DOI: 10.1016/j.gim.2025.101626
Yuchen Chang , Emma M. Rath , Magdalena Soka , Emma S. Singer , Gunjan Trivedi , Charlotte Burns , Rachel Austin , Tiffany Boughtwood , Jaye S. Brown , Sarah Casauria , Belinda Chong , Jasmina Cvetkovska , Sally L. Dunwoodie , Sebastian Lunke , Tessa Mattiske , Julie McGaughran , Sarah-Jane Pantaleo , Michael C.J. Quinn , Chris Semsarian , Ivan Macciocca , Zornitza Stark
Purpose
The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants.
Methods
Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes.
Results
A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, TBX20.
Conclusion
Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.
{"title":"Increased yield of genetic diagnoses in inherited heart diseases using expanded genome and RNA-splicing analyses","authors":"Yuchen Chang , Emma M. Rath , Magdalena Soka , Emma S. Singer , Gunjan Trivedi , Charlotte Burns , Rachel Austin , Tiffany Boughtwood , Jaye S. Brown , Sarah Casauria , Belinda Chong , Jasmina Cvetkovska , Sally L. Dunwoodie , Sebastian Lunke , Tessa Mattiske , Julie McGaughran , Sarah-Jane Pantaleo , Michael C.J. Quinn , Chris Semsarian , Ivan Macciocca , Zornitza Stark","doi":"10.1016/j.gim.2025.101626","DOIUrl":"10.1016/j.gim.2025.101626","url":null,"abstract":"<div><h3>Purpose</h3><div>The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants.</div></div><div><h3>Methods</h3><div>Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes.</div></div><div><h3>Results</h3><div>A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, <em>TBX20</em>.</div></div><div><h3>Conclusion</h3><div>Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101626"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421125","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 : 2026-01-01Epub Date: 2025-10-30DOI: 10.1016/j.gim.2025.101629
Jaime E. Hale , Brian P. O’Sullivan , Richard B. Parad , Henry L. Dorkin , Ted M. Kremer , Nico W. Vehse , Lael M. Yonker , Gregory S. Sawicki , Anne M. Counihan , Jacalyn Gerstel-Thompson , Binod Kumar , Anne Marie Comeau
Purpose
We seek to understand the incremental value of applying expanded variant panels or sequencing in population-based screening algorithms for a well-understood condition, such as cystic fibrosis (CF). We compared newborn screening methods to determine at what point do attempts to increase sensitivity of second-tier testing meet diminishing returns.
Methods
Using the genotypes of all Massachusetts CF-affected patients who were born between February 1, 1999 and January 31, 2024, we retrospectively applied screening algorithms that used (1) 39 CF gene (CFTR) variants, 139 CFTR variants, or CFTR sequencing and (2) different algorithms for referral to CF Center. Sensitivity, specificity, and timing of diagnosis were evaluated.
Results
Our current 39 CFTR variant panel and referral algorithm yielded a clinical sensitivity of 98.7%. In Massachusetts, expanding the variant panel might result in limited sensitivity improvement, but if the referral algorithm requires detection of 2 CFTR variants, it might decrease the sensitivity.
Conclusion
Expanding the CFTR variants genotyped does not necessarily guarantee an increase in screening sensitivity. Using a conservative cutoff for DNA testing might accomplish as much. Screening turnaround time, costs, and geographic location of CF Centers should be factored into decisions about the benefit of NGS technology within newborn screening.
{"title":"Expansion of variant panels in newborn screening algorithms to identify cystic fibrosis: A retrospective analysis of 25 years of genotypes and implications on diagnosis","authors":"Jaime E. Hale , Brian P. O’Sullivan , Richard B. Parad , Henry L. Dorkin , Ted M. Kremer , Nico W. Vehse , Lael M. Yonker , Gregory S. Sawicki , Anne M. Counihan , Jacalyn Gerstel-Thompson , Binod Kumar , Anne Marie Comeau","doi":"10.1016/j.gim.2025.101629","DOIUrl":"10.1016/j.gim.2025.101629","url":null,"abstract":"<div><h3>Purpose</h3><div>We seek to understand the incremental value of applying expanded variant panels or sequencing in population-based screening algorithms for a well-understood condition, such as cystic fibrosis (CF). We compared newborn screening methods to determine at what point do attempts to increase sensitivity of second-tier testing meet diminishing returns.</div></div><div><h3>Methods</h3><div>Using the genotypes of all Massachusetts CF-affected patients who were born between February 1, 1999 and January 31, 2024, we retrospectively applied screening algorithms that used (1) 39 CF gene (<em>CFTR</em>) variants, 139 <em>CFTR</em> variants, or <em>CFTR</em> sequencing and (2) different algorithms for referral to CF Center. Sensitivity, specificity, and timing of diagnosis were evaluated.</div></div><div><h3>Results</h3><div>Our current 39 <em>CFTR</em> variant panel and referral algorithm yielded a clinical sensitivity of 98.7%. In Massachusetts, expanding the variant panel might result in limited sensitivity improvement, but if the referral algorithm requires detection of 2 <em>CFTR</em> variants, it might decrease the sensitivity.</div></div><div><h3>Conclusion</h3><div>Expanding the <em>CFTR</em> variants genotyped does not necessarily guarantee an increase in screening sensitivity. Using a conservative cutoff for DNA testing might accomplish as much. Screening turnaround time, costs, and geographic location of CF Centers should be factored into decisions about the benefit of NGS technology within newborn screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101629"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426844","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 : 2026-01-01Epub Date: 2026-01-06DOI: 10.1016/j.gim.2025.101617
Taylor Kane , Tanner F. Coleman
{"title":"Correspondence on “Patterns of X-linked inheritance: A new approach for the genome era” by Basava et al","authors":"Taylor Kane , Tanner F. Coleman","doi":"10.1016/j.gim.2025.101617","DOIUrl":"10.1016/j.gim.2025.101617","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101617"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932956","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 : 2026-01-01Epub Date: 2025-10-25DOI: 10.1016/j.gim.2025.101624
Amicia Phillips , Maria Siermann , Zoë Claesen-Bengtson , Leigh Jackson , Caroline F. Wright
{"title":"What do we mean by actionability? Examining a key criterion in genomic prenatal and newborn screening","authors":"Amicia Phillips , Maria Siermann , Zoë Claesen-Bengtson , Leigh Jackson , Caroline F. Wright","doi":"10.1016/j.gim.2025.101624","DOIUrl":"10.1016/j.gim.2025.101624","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101624"},"PeriodicalIF":6.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145388456","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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