Pub Date : 2025-11-20DOI: 10.1016/j.gim.2025.101649
Maria Francesca Di Feo, Ida Paramonov, Leslie Matalonga Borrel, Ana Töpf, Alexander Hoischen, Sergi Beltran, Holm Graessner, Lisenka Vissers, Richarda de Voer, Marielle van Gijn, Simona Balestrini, Holger Lerche, Gaëtan Lesca, Swethaa Natraj Gayathri, Kornelia Ellwanger, Mireille Cossee, Aurelien Perrin, Anna Sarkozy, Gisele Bonne, Job A J Verdonschot, German Demidov, Steven Laurie, Mridul Johari, Peter Hackman, Marco Savarese, Bjarne Udd
Purpose: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases.
Methods: We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature.
Results: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy.
Conclusion: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.
{"title":"The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.","authors":"Maria Francesca Di Feo, Ida Paramonov, Leslie Matalonga Borrel, Ana Töpf, Alexander Hoischen, Sergi Beltran, Holm Graessner, Lisenka Vissers, Richarda de Voer, Marielle van Gijn, Simona Balestrini, Holger Lerche, Gaëtan Lesca, Swethaa Natraj Gayathri, Kornelia Ellwanger, Mireille Cossee, Aurelien Perrin, Anna Sarkozy, Gisele Bonne, Job A J Verdonschot, German Demidov, Steven Laurie, Mridul Johari, Peter Hackman, Marco Savarese, Bjarne Udd","doi":"10.1016/j.gim.2025.101649","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101649","url":null,"abstract":"<p><strong>Purpose: </strong>Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases.</p><p><strong>Methods: </strong>We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature.</p><p><strong>Results: </strong>Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy.</p><p><strong>Conclusion: </strong>This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101649"},"PeriodicalIF":6.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145587150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.gim.2025.101640
Jessica Le Gall , Catherine Dehainault , Ambre Petitalot , Elsa Amouyal , Jeanne Petitou , Sandrine M. Caputo , François Radvanyi , Alexandre Matet , Nathalie Cassoux , Livia Lumbroso-Le Rouic , Isabelle Aerts , François Doz , Marion Gauthier-Villars , Dominique Stoppa-Lyonnet , Claude Houdayer , Lisa Golmard , François Lallemand
Purpose
The RB1 gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the RB1 gene predisposing to retinoblastoma and other tumors. By analyzing the RB1 gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS).
Methods
To classify RB1 VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the E2F1 promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign RB1 variants was used for validation.
Results
We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit E2F1 promoter. Among them, the (RB1) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic.
Conclusion
This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic RB1 variants.
目的：RB1基因编码视网膜母细胞瘤蛋白（pRB），在细胞周期控制中发挥重要作用，特别是通过其与E2F转录因子的相互作用。家族性视网膜母细胞瘤是由RB1基因的种系致病性变异引起的，易导致视网膜母细胞瘤和其他肿瘤。通过分析视网膜母细胞瘤患者的RB1基因，错义变异通常仍然是不确定意义的变异（VUS）。方法：为了对RB1 VUS进行分类，我们开发了一种功能分析方法，评估它们对pRB抑制E2F1启动子活性的能力的影响，该能力具有荧光素酶报告基因。一组14个致病性/可能致病性和良性/可能良性的RB1变异被用于验证。结果：我们检测了视网膜母细胞瘤患者中检测到的16个VUS，发现9个VUS降低了pRB抑制E2F1启动子的能力。其中，（RB1） c. 2263T>G . p.（Phe755Val）变异在Western Blot上显示pRB水平降低，提示pRB稳定性存在缺陷。通过将ACMG/AMP分类的PS3_moderate标准应用于该功能分析，9个具有功能影响的VUS中有5个可归类为可能致病。结论：该功能检测可以通过更好地确定致病性/可能致病性RB1变异来提高视网膜母细胞瘤易感性的分子诊断。
{"title":"A functional assay to classify RB1 variants of uncertain significance","authors":"Jessica Le Gall , Catherine Dehainault , Ambre Petitalot , Elsa Amouyal , Jeanne Petitou , Sandrine M. Caputo , François Radvanyi , Alexandre Matet , Nathalie Cassoux , Livia Lumbroso-Le Rouic , Isabelle Aerts , François Doz , Marion Gauthier-Villars , Dominique Stoppa-Lyonnet , Claude Houdayer , Lisa Golmard , François Lallemand","doi":"10.1016/j.gim.2025.101640","DOIUrl":"10.1016/j.gim.2025.101640","url":null,"abstract":"<div><h3>Purpose</h3><div>The <em>RB1</em> gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the <em>RB1</em> gene predisposing to retinoblastoma and other tumors. By analyzing the <em>RB1</em> gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS).</div></div><div><h3>Methods</h3><div>To classify <em>RB1</em> VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the <em>E2F1</em> promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign <em>RB1</em> variants was used for validation.</div></div><div><h3>Results</h3><div>We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit <em>E2F1</em> promoter. Among them, the (<em>RB1</em>) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic.</div></div><div><h3>Conclusion</h3><div>This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic <em>RB1</em> variants.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101640"},"PeriodicalIF":6.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530624","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}
Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.
Methods
RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.
Results
Since its launch, and at the time of this report, RARE-X has enrolled 7493 participants from 93 countries, including 3857 patients and 3636 caregivers or siblings, across 74 rare disease communities supported by more than 120 Patient Advocacy Groups. Sixty-three percent are US-based and 37% international. Data are used in research applications, community reporting, and computational analyses.
Conclusion
RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with the potential to inform therapeutic development and advance rare disease research.
{"title":"RARE-X: A patient-driven approach for collecting symptom and patient-reported outcome data in rare diseases","authors":"Vanessa Vogel-Farley , Karmen Trzupek , Jade Gosar , Katelyn Hobbs , Kelly Wentworth , Bridget Michaels , Geoffrey Beek , Tina Dang , Mackenzie Abramson , Megan O’Boyle , Nicole Boice , Charlene Son Rigby , Zohreh Talebizadeh","doi":"10.1016/j.gim.2025.101634","DOIUrl":"10.1016/j.gim.2025.101634","url":null,"abstract":"<div><h3>Purpose</h3><div>Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.</div></div><div><h3>Methods</h3><div>RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.</div></div><div><h3>Results</h3><div>Since its launch, and at the time of this report, RARE-X has enrolled 7493 participants from 93 countries, including 3857 patients and 3636 caregivers or siblings, across 74 rare disease communities supported by more than 120 Patient Advocacy Groups. Sixty-three percent are US-based and 37% international. Data are used in research applications, community reporting, and computational analyses.</div></div><div><h3>Conclusion</h3><div>RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with the potential to inform therapeutic development and advance rare disease research.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101634"},"PeriodicalIF":6.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1016/j.gim.2025.101635
Annie D. Niehaus , David A. Stevenson , Miriam G. Blitzer
Purpose
This report analyzes Medical Genetics and Genomics (MGG) training trends from 2015 to 2024. Understanding such trends is vital for developing targeted recruitment and workforce development initiatives.
Methods
Matriculation data from the American Board of Medical Genetics and Genomics (ABMGG) and publicly available data from the National Resident Matching Program (NRMP) Main Residency and Specialty Matches were reviewed. Descriptive statistics and linear regression analysis were used to compare growth among MGG training pathways and to analyze trends.
Results
From 2015 to 2024, there has been a small, but not statistically significant, increase in the total number of individuals who have matched into categorical MGG, combined Pediatrics (Peds)-MGG, and combined Internal Medicine (IM)-MGG residency programs as a whole. This has been driven by an increase in the number of matches to combined Peds-MGG programs. Matriculation into training programs has exceeded the number of matches in categorical MGG as some positions have been filled outside of the NRMP Match. The average match rate for all applicants in categorical MGG (87%) has been higher than that for Peds-MGG (52%).
Conclusion
Growth in applicants to combined programs and matriculation into residency programs after the NRMP Match has been promising; however, these increases are not enough to fulfill growing workforce demands.
{"title":"Medical genetics and genomics residency programs: Trends in applications, match rates, and matriculation from 2015 to 2024","authors":"Annie D. Niehaus , David A. Stevenson , Miriam G. Blitzer","doi":"10.1016/j.gim.2025.101635","DOIUrl":"10.1016/j.gim.2025.101635","url":null,"abstract":"<div><h3>Purpose</h3><div>This report analyzes Medical Genetics and Genomics (MGG) training trends from 2015 to 2024. Understanding such trends is vital for developing targeted recruitment and workforce development initiatives.</div></div><div><h3>Methods</h3><div>Matriculation data from the American Board of Medical Genetics and Genomics (ABMGG) and publicly available data from the National Resident Matching Program (NRMP) Main Residency and Specialty Matches were reviewed. Descriptive statistics and linear regression analysis were used to compare growth among MGG training pathways and to analyze trends.</div></div><div><h3>Results</h3><div>From 2015 to 2024, there has been a small, but not statistically significant, increase in the total number of individuals who have matched into categorical MGG, combined Pediatrics (Peds)-MGG, and combined Internal Medicine (IM)-MGG residency programs as a whole. This has been driven by an increase in the number of matches to combined Peds-MGG programs. Matriculation into training programs has exceeded the number of matches in categorical MGG as some positions have been filled outside of the NRMP Match. The average match rate for all applicants in categorical MGG (87%) has been higher than that for Peds-MGG (52%).</div></div><div><h3>Conclusion</h3><div>Growth in applicants to combined programs and matriculation into residency programs after the NRMP Match has been promising; however, these increases are not enough to fulfill growing workforce demands.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101635"},"PeriodicalIF":6.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.gim.2025.101631
Aantaki Raisa , Irania Santaliz Moreno , Amy Ayala , Jada G. Hamilton , Jessica Mozersky , Erin Linnenbringer , Julia Maki , Amy McQueen , George P. Souroullas , Erika A. Waters
Purpose
This study aimed to explore how health-related epigenetic concepts are depicted in YouTube videos, a widely accessed platform for informal science education. As epigenetics becomes increasingly relevant to medical therapeutics, it is essential to understand what information is being disseminated in the public sphere.
Methods
We conducted a content analysis of 296 YouTube videos about epigenetics that were under 10 minutes in length. We transcribed and analyzed the videos using an iteratively developed codebook and then categorized relevant codes as categories.
Results
We identified 7 categories: (1) defining epigenetics, (2) causes of epigenetic changes, (3) effects of epigenetic change, (4) epigenetic inheritability, (5) application of epigenetics, (6) personal control, and (7) epigenetic mysticism. Although the content about the molecular epigenetic mechanisms mostly aligned with the latest scientific findings, there were numerous unsubstantiated and exaggerated claims about effects of epigenetics on human health, especially disease outcomes.
Conclusion
We identified several scientific concepts described on YouTube regarding epigenetics. Our findings also reveal what information about epigenetics is widely shared in the public sphere, helping to identify key misconceptions to address and guiding the development of strategies for accurate scientific communication.
{"title":"A content analysis of health-related epigenetic information in YouTube videos","authors":"Aantaki Raisa , Irania Santaliz Moreno , Amy Ayala , Jada G. Hamilton , Jessica Mozersky , Erin Linnenbringer , Julia Maki , Amy McQueen , George P. Souroullas , Erika A. Waters","doi":"10.1016/j.gim.2025.101631","DOIUrl":"10.1016/j.gim.2025.101631","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to explore how health-related epigenetic concepts are depicted in YouTube videos, a widely accessed platform for informal science education. As epigenetics becomes increasingly relevant to medical therapeutics, it is essential to understand what information is being disseminated in the public sphere.</div></div><div><h3>Methods</h3><div>We conducted a content analysis of 296 YouTube videos about epigenetics that were under 10 minutes in length. We transcribed and analyzed the videos using an iteratively developed codebook and then categorized relevant codes as categories.</div></div><div><h3>Results</h3><div>We identified 7 categories: (1) defining epigenetics, (2) causes of epigenetic changes, (3) effects of epigenetic change, (4) epigenetic inheritability, (5) application of epigenetics, (6) personal control, and (7) epigenetic mysticism. Although the content about the molecular epigenetic mechanisms mostly aligned with the latest scientific findings, there were numerous unsubstantiated and exaggerated claims about effects of epigenetics on human health, especially disease outcomes.</div></div><div><h3>Conclusion</h3><div>We identified several scientific concepts described on YouTube regarding epigenetics. Our findings also reveal what information about epigenetics is widely shared in the public sphere, helping to identify key misconceptions to address and guiding the development of strategies for accurate scientific communication.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101631"},"PeriodicalIF":6.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470881","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 : 2025-10-30DOI: 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":"2025-10-30","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 : 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":"2025-10-29","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 : 2025-10-25DOI: 10.1016/j.gim.2025.101624
Amicia Phillips , Maria Siermann , Zoë Claesen-Bengtson , Leigh Jackson , Caroline F. Wright
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Pub Date : 2025-10-25DOI: 10.1016/j.gim.2025.101625
Tehmeena Akhter , Zubair M. Ahmed , Yaping Ji , Axel Schmidt , Meron Azage , Maria Palomares , Kirsten Cremer , Hartmut Engels , Jennifer O. Murphy , Sophia Peters , Elisabeth Mangold , M.L.Á. Gomez-Cano , Rodney J. Taylor , Sheikh Riazuddin , Saima Riazuddin
Purpose
Neurodevelopmental disorders (NDDs) are characterized by limitations in brain development. This study aims to determine the genetic causes of NDD in humans.
Methods
Exome sequencing was used to detect genetic variants of KLHL13, which encodes Kelch like protein 13 (KLHL13), in four families segregating in an X-linked pattern. In silico protein modeling and overexpression in heterologous cells were used to determine the variant’s impact. klhl13 loss of function was modeled in zebrafish, followed by rescue studies using human KLHL13 messenger RNA (mRNA) and an Aurora Kinase B (AURKB) inhibitor.
Results
We found one frameshift and three missense hemizygous variants of KLHL13 in individuals exhibiting NDD characteristics, such as intellectual disability (ID) and macrocephaly. Three-dimensional protein modeling simulation predicted the alteration of the KLHL13 protein folding for missense variants. Overexpression of NDD-associated variants in HEK293T cells revealed a significant impact on KLHL13-mediated cell-cycle regulation during mitosis, leading to genomic instability. Knocking down klhl13 in zebrafish resulted in developmental deficits, which were rescued by coinjection of human KLHL13WT messenger RNA but not by transcript encoding NDD variants. Treatment with AURKB selective inhibitor AZD1152-HQPA rescued genomic stability in heterologous cells and neurobehavioral deficits in zebrafish.
Conclusion
Our results implicate KLHL13-mediated AURKB regulation as a significant contributor to NDD in humans. Inhibiting AURKB activity could serve as a potential therapeutic approach to improve brain development and cognitive function.
{"title":"KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models","authors":"Tehmeena Akhter , Zubair M. Ahmed , Yaping Ji , Axel Schmidt , Meron Azage , Maria Palomares , Kirsten Cremer , Hartmut Engels , Jennifer O. Murphy , Sophia Peters , Elisabeth Mangold , M.L.Á. Gomez-Cano , Rodney J. Taylor , Sheikh Riazuddin , Saima Riazuddin","doi":"10.1016/j.gim.2025.101625","DOIUrl":"10.1016/j.gim.2025.101625","url":null,"abstract":"<div><h3>Purpose</h3><div>Neurodevelopmental disorders (NDDs) are characterized by limitations in brain development. This study aims to determine the genetic causes of NDD in humans.</div></div><div><h3>Methods</h3><div>Exome sequencing was used to detect genetic variants of <em>KLHL13,</em> which encodes Kelch like protein 13 (KLHL13), in four families segregating in an X-linked pattern. <em>In silico</em> protein modeling and overexpression in heterologous cells were used to determine the variant’s impact. <em>klhl13</em> loss of function was modeled in zebrafish, followed by rescue studies using human <em>KLHL13</em> messenger RNA (mRNA) and an Aurora Kinase B (AURKB) inhibitor.</div></div><div><h3>Results</h3><div>We found one frameshift and three missense hemizygous variants of <em>KLHL13</em> in individuals exhibiting NDD characteristics, such as intellectual disability (ID) and macrocephaly. Three-dimensional protein modeling simulation predicted the alteration of the KLHL13 protein folding for missense variants. Overexpression of NDD-associated variants in HEK293T cells revealed a significant impact on KLHL13-mediated cell-cycle regulation during mitosis, leading to genomic instability. Knocking down <em>klhl13</em> in zebrafish resulted in developmental deficits, which were rescued by coinjection of human <em>KLHL13</em><sup>WT</sup> messenger RNA but not by transcript encoding NDD variants. Treatment with AURKB selective inhibitor AZD1152-HQPA rescued genomic stability in heterologous cells and neurobehavioral deficits in zebrafish.</div></div><div><h3>Conclusion</h3><div>Our results implicate KLHL13-mediated AURKB regulation as a significant contributor to NDD in humans. Inhibiting AURKB activity could serve as a potential therapeutic approach to improve brain development and cognitive function.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101625"},"PeriodicalIF":6.2,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145388502","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 : 2025-10-24DOI: 10.1016/j.gim.2025.101618
Lilian Downie , Julie Yeo , Thomas Minten , Rose Heald , Derek Ansel , Mei Baker , Jorune Balciuniene , Jonathan S. Berg , François Boemer , Wendy K. Chung , Heidi L. Cope , David J. Eckstein , Nicolas Encina , Laurence Faivre , Alessandra Ferlini , Judit García-Villoria , Michael H. Gelb , José Manuel González De Aledo-Castillo , Katie Golden-Grant , Richard B. Parad , Nina B. Gold
Purpose
For decades, the selection of disorders included in newborn screening (NBS) programs has been guided by principles published by Wilson and Jungner in 1968. As research explores the expansion of conditions included in NBS through genomic sequencing, there is a critical need for updated recommendations to address the opportunities and complexities of genomic data.
Methods
The International Consortium on Newborn Sequencing includes leaders from over 16 research projects investigating genomic NBS across the United Kingdom, Europe, United States, and Oceania. Consortium members were invited to participate in a modified Delphi study, aggregating opinion on the selection of conditions for genomic NBS through 3 rounds of online questionnaires, with feedback provided to participants between rounds.
Results
In round 1, 94 participants completed the questionnaire, and 10 of 43 statements reached consensus. In round 2, 81 participants completed the questionnaire, and 14 of 27 statements reached consensus. In round 3, 68 participants completed the questionnaire, and all 10 statements reached 72% or more consensus.
Conclusion
The 10 consensus recommendations developed in this study can guide future research and public health programs performing genomic NBS. This process also identified key areas of participant discordance, highlighting important topics for future research.
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