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
{"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":"2025-10-25","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}
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.
{"title":"Operationalizing the Wilson-Jungner principles for the genomics era: Consensus recommendations from the International Consortium on Newborn Sequencing","authors":"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","doi":"10.1016/j.gim.2025.101618","DOIUrl":"10.1016/j.gim.2025.101618","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101618"},"PeriodicalIF":6.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577363","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.2025.101623
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":"2025-10-24","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 : 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":"2025-10-24","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 : 2025-10-24DOI: 10.1016/j.gim.2025.101621
Gert de Graaf , Frank Buckley , Brian G. Skotko
Purpose
We estimate the live births and overall population with Down syndrome (DS) in Latin America and the Caribbean from 1950 to 2020. This study adds to previous work from the United States, Europe, Australia, New Zealand, and Canada.
Methods
We used a validated model, adjusted for the region, to estimate live birth prevalence, population prevalence, and life expectancy of people with DS, utilizing data from the UN World Population Prospects and other sources.
Results
We estimate 18,655 (95% CI: 18,387-18,923) annual live births of children with DS (2016-2020) in Latin America and the Caribbean (18.4 per 10,000 live births, 95% CI: 18.2-18.7). The estimated total population of people with DS was 574,092 (95% CI: 572,607-575,577) in 2020 (8.8 per 10,000 inhabitants, 95% CI: 8.78-8.83). Mean life expectancy increased from 10 years in 1950 to 48 years in 2020.
Conclusion
In Latin America and the Caribbean, the overall population of people with DS is still growing significantly. This is due to sharply increasing survival rates for children with DS in recent decades, combined with relatively few selective abortions in this region.
{"title":"Estimation of the number of people with Down syndrome in Latin America and the Caribbean","authors":"Gert de Graaf , Frank Buckley , Brian G. Skotko","doi":"10.1016/j.gim.2025.101621","DOIUrl":"10.1016/j.gim.2025.101621","url":null,"abstract":"<div><h3>Purpose</h3><div>We estimate the live births and overall population with Down syndrome (DS) in Latin America and the Caribbean from 1950 to 2020. This study adds to previous work from the United States, Europe, Australia, New Zealand, and Canada.</div></div><div><h3>Methods</h3><div>We used a validated model, adjusted for the region, to estimate live birth prevalence, population prevalence, and life expectancy of people with DS, utilizing data from the UN World Population Prospects and other sources.</div></div><div><h3>Results</h3><div>We estimate 18,655 (95% CI: 18,387-18,923) annual live births of children with DS (2016-2020) in Latin America and the Caribbean (18.4 per 10,000 live births, 95% CI: 18.2-18.7). The estimated total population of people with DS was 574,092 (95% CI: 572,607-575,577) in 2020 (8.8 per 10,000 inhabitants, 95% CI: 8.78-8.83). Mean life expectancy increased from 10 years in 1950 to 48 years in 2020.</div></div><div><h3>Conclusion</h3><div>In Latin America and the Caribbean, the overall population of people with DS is still growing significantly. This is due to sharply increasing survival rates for children with DS in recent decades, combined with relatively few selective abortions in this region.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101621"},"PeriodicalIF":6.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620927","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.2025.101620
Thiloka Ratnaike , Siddharth Ramanan , Nour Elkhateeb , Ramya Narayanan , Jenny Yang , Eszter Sara Arany , Manya Mirchandani , Rachael Piper , Katherine Schon , M. Eren Kule , Christopher Gilmartin , Angela Lochmüller , Emogene Shaw , Rita Horváth , Patrick F. Chinnery
Purpose
Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
Methods
Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
Results
MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
Conclusion
MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.
{"title":"Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants","authors":"Thiloka Ratnaike , Siddharth Ramanan , Nour Elkhateeb , Ramya Narayanan , Jenny Yang , Eszter Sara Arany , Manya Mirchandani , Rachael Piper , Katherine Schon , M. Eren Kule , Christopher Gilmartin , Angela Lochmüller , Emogene Shaw , Rita Horváth , Patrick F. Chinnery","doi":"10.1016/j.gim.2025.101620","DOIUrl":"10.1016/j.gim.2025.101620","url":null,"abstract":"<div><h3>Purpose</h3><div>Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the <em>MitoPhen</em> database to characterize phenotypic variation across PMD more systematically.</div></div><div><h3>Methods</h3><div>Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce <em>MitoPhen v2</em>. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.</div></div><div><h3>Results</h3><div><em>MitoPhen v2</em> adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using <em>MT-TL1</em>, single large-scale mitochondrial DNA deletions, and <em>POLG</em> as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.</div></div><div><h3>Conclusion</h3><div><em>MitoPhen v2</em> enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 1","pages":"Article 101620"},"PeriodicalIF":6.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577362","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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