Pub Date : 2025-10-23DOI: 10.1038/s41431-025-01964-0
Leon Chang, James A. Poulter, Andrew R. Webster, Gavin Arno, Rajarshi Mukherjee, Andrew Lotery, Alison J. Hardcastle, Christopher M. Watson, Chris F. Inglehearn
Variants in six pre-mRNA processing factors cause autosomal dominant Retinitis Pigmentosa (adRP). The RP9 gene encodes a seventh splicing factor, and in 2002, we published RP9 variants c.410A>T; p.(H137L) and c.509A>G; p.(D170G) as likely causes of adRP in a large multigenerational RP9-linked family and a single case, respectively. It has since been suggested these variants might be artefacts due to simultaneous amplification of the RP9P pseudogene, and no further pathogenic variants have been reported. We therefore rescreened two members of the RP9-linked family by genome sequencing. Examination of the 2 Mb locus defined by crossovers in the original family revealed no other plausible causative variants. Alignment of both short and long-read sequences confirmed that p.(H137L) is in the RP9 gene, not the pseudogene. Screening for p.(H137L) in 1961 RP/Rod-cone dystrophy (RCD) cases from the Leeds patient cohort and UK 100,000 Genomes Project (100kGP) database revealed four further carriers. Including the original family, this variant was therefore present in 5/1962 RP/RCD probands, and is absent from gnomAD, constituting statistically significant enrichment in RP cases. Long-read sequencing of p.(H137L) in available carriers showed this is a UK founder allele. The RP9 p.(D170G) allele was also confirmed as gene, not pseudogene, derived, but is present in 22 individuals in the 100kGP cohort, none with RP, as well as >200 individuals in gnomAD and Biobank, suggesting it is non-pathogenic. In conclusion, RP9 p.(H137L) is strongly associated with RP and remains the only plausible variant accounting for the condition in a large multi-generation adRP family.
{"title":"RP9 revisited; RP9 p.(H137L) remains a likely cause of dominant splicing factor-Retinitis Pigmentosa","authors":"Leon Chang, James A. Poulter, Andrew R. Webster, Gavin Arno, Rajarshi Mukherjee, Andrew Lotery, Alison J. Hardcastle, Christopher M. Watson, Chris F. Inglehearn","doi":"10.1038/s41431-025-01964-0","DOIUrl":"10.1038/s41431-025-01964-0","url":null,"abstract":"Variants in six pre-mRNA processing factors cause autosomal dominant Retinitis Pigmentosa (adRP). The RP9 gene encodes a seventh splicing factor, and in 2002, we published RP9 variants c.410A>T; p.(H137L) and c.509A>G; p.(D170G) as likely causes of adRP in a large multigenerational RP9-linked family and a single case, respectively. It has since been suggested these variants might be artefacts due to simultaneous amplification of the RP9P pseudogene, and no further pathogenic variants have been reported. We therefore rescreened two members of the RP9-linked family by genome sequencing. Examination of the 2 Mb locus defined by crossovers in the original family revealed no other plausible causative variants. Alignment of both short and long-read sequences confirmed that p.(H137L) is in the RP9 gene, not the pseudogene. Screening for p.(H137L) in 1961 RP/Rod-cone dystrophy (RCD) cases from the Leeds patient cohort and UK 100,000 Genomes Project (100kGP) database revealed four further carriers. Including the original family, this variant was therefore present in 5/1962 RP/RCD probands, and is absent from gnomAD, constituting statistically significant enrichment in RP cases. Long-read sequencing of p.(H137L) in available carriers showed this is a UK founder allele. The RP9 p.(D170G) allele was also confirmed as gene, not pseudogene, derived, but is present in 22 individuals in the 100kGP cohort, none with RP, as well as >200 individuals in gnomAD and Biobank, suggesting it is non-pathogenic. In conclusion, RP9 p.(H137L) is strongly associated with RP and remains the only plausible variant accounting for the condition in a large multi-generation adRP family.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"227-235"},"PeriodicalIF":4.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01964-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1038/s41431-025-01967-x
Claudio Peter D’Incal, Bram Dierickx, Claudia Vingerhoets, Mieke van Haelst, Dale John Annear, Anke Van Dijck, Lina Bastini, Anthony Konings, Ellen Elinck, Ligia Mateiu, Agnies M. van Eeghen, R. Frank Kooy
The majority of patients affected by fragile X syndrome (OMIM #300624), a common inherited form of autism spectrum disorders and intellectual disability, displays a CGG triplet repeat expansion in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene promotor, resulting in hypermethylation and epigenetic silencing of the associated FMRP protein. Only a handful of missense variants have been described as causative for fragile X syndrome and only the p.Arg138Gln variant has been reported as recurrent. Here, we present a 23-year-old male subject with the clinical characteristics of fragile X syndrome who is diagnosed with the maternally inherited missense variant c.500A>C, that translates proline at amino acid residue 167 instead of glutamic acid (p.Gln167Pro), but without an FMR1 repeat expansion. Western blotting experiments demonstrated that the Gln167Pro mutant showed a remarkable reduction of FMRP expression in lymphoblastoid cell lines, paralleled by similar observations in a HEK293T overexpression system. Subsequent lymphoblastoid transcriptome analysis showed a dysregulated gene signature with significant overlap with that observed in patients with a fragile X repeat expansion. Genome-wide methylation analysis confirmed hypomethylation of the FMR1 promotor region, indicative for expression of the gene. This report suggests that the FMR1 c.500A>C (p.Gln167Pro) missense variant is causative for a fragile X syndrome phenotype with a disrupted molecular gene signature characteristic for the syndrome and illustrates the use of an ID gene panel as a complementary diagnostic tool in case of a negative CGG repeat expansion test.
{"title":"A missense variant in the KH0-domain of FMRP downregulates the protein in a patient with the clinical hallmarks of fragile X syndrome","authors":"Claudio Peter D’Incal, Bram Dierickx, Claudia Vingerhoets, Mieke van Haelst, Dale John Annear, Anke Van Dijck, Lina Bastini, Anthony Konings, Ellen Elinck, Ligia Mateiu, Agnies M. van Eeghen, R. Frank Kooy","doi":"10.1038/s41431-025-01967-x","DOIUrl":"10.1038/s41431-025-01967-x","url":null,"abstract":"The majority of patients affected by fragile X syndrome (OMIM #300624), a common inherited form of autism spectrum disorders and intellectual disability, displays a CGG triplet repeat expansion in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene promotor, resulting in hypermethylation and epigenetic silencing of the associated FMRP protein. Only a handful of missense variants have been described as causative for fragile X syndrome and only the p.Arg138Gln variant has been reported as recurrent. Here, we present a 23-year-old male subject with the clinical characteristics of fragile X syndrome who is diagnosed with the maternally inherited missense variant c.500A>C, that translates proline at amino acid residue 167 instead of glutamic acid (p.Gln167Pro), but without an FMR1 repeat expansion. Western blotting experiments demonstrated that the Gln167Pro mutant showed a remarkable reduction of FMRP expression in lymphoblastoid cell lines, paralleled by similar observations in a HEK293T overexpression system. Subsequent lymphoblastoid transcriptome analysis showed a dysregulated gene signature with significant overlap with that observed in patients with a fragile X repeat expansion. Genome-wide methylation analysis confirmed hypomethylation of the FMR1 promotor region, indicative for expression of the gene. This report suggests that the FMR1 c.500A>C (p.Gln167Pro) missense variant is causative for a fragile X syndrome phenotype with a disrupted molecular gene signature characteristic for the syndrome and illustrates the use of an ID gene panel as a complementary diagnostic tool in case of a negative CGG repeat expansion test.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1596-1605"},"PeriodicalIF":4.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1038/s41431-025-01959-x
Daphne J. Smits, Federico Ferraro, Mark Drost, Herma C. van der Linde, Bianca M. de Graaf, Yolande van Bever, Alice S. Brooks, Livija Bardina, Hennie T. Brüggenwirth, Christophe Debuy, Laura Donker Kaat, Bastiaan T. van Dijk, Nienke van Engelen, Geert Geeven, Raoul van de Graaf, Désirée Y. van Haaften-Visser, Peter M. van Hasselt, Daphne Heijsman, Yvonne M. C. Hendriks, Rebekkah J. Hitti-Malin, Lies H. Hoefsloot, Glenn Huijbregts, Hanna IJspeert, Sander Lamballais, Jona Mijalkovic, Merel O. Mol, Diënna Nawawi, Nadine Nederpelt, Esther A. R. Nibbeling, Wouter te Rijdt, Rachel Schot, Marjon van Slegtenhorst, Frank Sleutels, Eva L. M. Ulenkate, Monique Van Veghel – Plandsoen, Judith M. A. Verhagen, David Vos, Erwin Wauters, Martina Wilke, Marc Sylva, Tahsin Stefan Barakat, Tjakko J. van Ham, Tjitske Kleefstra, Dmitrijs Rots, Virginie J. M. Verhoeven
Critically ill pediatric patients often have genetic disorders requiring a rapid diagnosis to guide urgent care decisions. Standard genetic testing typically takes weeks and requires multiple tests. Nanopore long-read genome sequencing (LR-GS) delivers genome-wide results within days as a one-test-fits-all solution. As one of the first centers in Europe, we implement ultrarapid LR-GS for critically ill patients. We enrolled 26 critically ill patients (median age 2 months) suspected of having a genetic disorder at the intensive care unit to perform (ultra)rapid nanopore LR-GS alongside standard genomic care. We compared diagnostic yield, turnaround time (TAT), and evaluated the impact on clinical decision making. In 11/26 cases a genetic diagnosis was made with (ultra)rapid LR-GS. From sample receipt to result, the average TAT was 5.3 days (range 2.0–10.8) for LR-GS and 18.4 days (range 6.1–29.1) for standard genomic care. DNA methylation analysis from LR-GS expedited the diagnosis in 3/26 cases. In 7/11 solved cases ultrarapid LR-GS led to immediate adjustments in patient care, e.g., medication switch or termination of treatment. Our findings underscore the clinical impact of ultrarapid LR-GS, including added value of methylation analysis, for critically ill patients and highlight existing challenges, paving the way to ultrarapid LR-GS integration into standard diagnostics.
{"title":"Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision making","authors":"Daphne J. Smits, Federico Ferraro, Mark Drost, Herma C. van der Linde, Bianca M. de Graaf, Yolande van Bever, Alice S. Brooks, Livija Bardina, Hennie T. Brüggenwirth, Christophe Debuy, Laura Donker Kaat, Bastiaan T. van Dijk, Nienke van Engelen, Geert Geeven, Raoul van de Graaf, Désirée Y. van Haaften-Visser, Peter M. van Hasselt, Daphne Heijsman, Yvonne M. C. Hendriks, Rebekkah J. Hitti-Malin, Lies H. Hoefsloot, Glenn Huijbregts, Hanna IJspeert, Sander Lamballais, Jona Mijalkovic, Merel O. Mol, Diënna Nawawi, Nadine Nederpelt, Esther A. R. Nibbeling, Wouter te Rijdt, Rachel Schot, Marjon van Slegtenhorst, Frank Sleutels, Eva L. M. Ulenkate, Monique Van Veghel – Plandsoen, Judith M. A. Verhagen, David Vos, Erwin Wauters, Martina Wilke, Marc Sylva, Tahsin Stefan Barakat, Tjakko J. van Ham, Tjitske Kleefstra, Dmitrijs Rots, Virginie J. M. Verhoeven","doi":"10.1038/s41431-025-01959-x","DOIUrl":"10.1038/s41431-025-01959-x","url":null,"abstract":"Critically ill pediatric patients often have genetic disorders requiring a rapid diagnosis to guide urgent care decisions. Standard genetic testing typically takes weeks and requires multiple tests. Nanopore long-read genome sequencing (LR-GS) delivers genome-wide results within days as a one-test-fits-all solution. As one of the first centers in Europe, we implement ultrarapid LR-GS for critically ill patients. We enrolled 26 critically ill patients (median age 2 months) suspected of having a genetic disorder at the intensive care unit to perform (ultra)rapid nanopore LR-GS alongside standard genomic care. We compared diagnostic yield, turnaround time (TAT), and evaluated the impact on clinical decision making. In 11/26 cases a genetic diagnosis was made with (ultra)rapid LR-GS. From sample receipt to result, the average TAT was 5.3 days (range 2.0–10.8) for LR-GS and 18.4 days (range 6.1–29.1) for standard genomic care. DNA methylation analysis from LR-GS expedited the diagnosis in 3/26 cases. In 7/11 solved cases ultrarapid LR-GS led to immediate adjustments in patient care, e.g., medication switch or termination of treatment. Our findings underscore the clinical impact of ultrarapid LR-GS, including added value of methylation analysis, for critically ill patients and highlight existing challenges, paving the way to ultrarapid LR-GS integration into standard diagnostics.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"108-118"},"PeriodicalIF":4.6,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01959-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1038/s41431-025-01960-4
Enrico Bertini
{"title":"Recessive variants in CACNB1: a new culprit in congenital myopathy. Expanding the genetic causes of excitation-contraction coupling disorders.","authors":"Enrico Bertini","doi":"10.1038/s41431-025-01960-4","DOIUrl":"https://doi.org/10.1038/s41431-025-01960-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase that plays significant roles in cell growth, proliferation, and differentiation. Germline variants of PDGFRB can lead to several different diseases, e.g. infantile myofibromatosis, Kosaki overgrowth syndrome, Penttinen premature aging syndrome, ocular pterygium – digital keloid dysplasia, primary familial brain calcification, and others. Some variants cause the kinase to be constitutively active, even in the absence of ligand, while others lead to inactivation of signaling transduction mechanisms. Constitutive activation of PDGFRβ leads to increased cell growth, proliferation, and differentiation, which can lead to the development of tumors or other abnormal growths. The development of new therapies that target PDGFRβ is an active area of research, primarily in cancer treatment. However, these therapies have the potential to also provide effective treatment options for patients with germline variants of PDGFRB. Here, we provide a summary of recurrent activating germline variants reported in PDGFRB and examine their sensitivity to different tyrosine kinase inhibitors. We show that the respective amino acid substitutions respond differently to treatment with tyrosine kinase inhibitors that correlate with previous in vivo data. Our data may assist healthcare providers when deciding personalized treatment of patients with disorders associated with activating variants in PDGFRB.
{"title":"Variable response of germline activating PDGFRB variants to receptor tyrosine kinase inhibitors: implications for treatment","authors":"Ileana Cristea, Roya Mehrasa, Titas Gladkauskas, Eyvind Rødahl, Ove Bruland, Cecilie Bredrup","doi":"10.1038/s41431-025-01958-y","DOIUrl":"10.1038/s41431-025-01958-y","url":null,"abstract":"Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase that plays significant roles in cell growth, proliferation, and differentiation. Germline variants of PDGFRB can lead to several different diseases, e.g. infantile myofibromatosis, Kosaki overgrowth syndrome, Penttinen premature aging syndrome, ocular pterygium – digital keloid dysplasia, primary familial brain calcification, and others. Some variants cause the kinase to be constitutively active, even in the absence of ligand, while others lead to inactivation of signaling transduction mechanisms. Constitutive activation of PDGFRβ leads to increased cell growth, proliferation, and differentiation, which can lead to the development of tumors or other abnormal growths. The development of new therapies that target PDGFRβ is an active area of research, primarily in cancer treatment. However, these therapies have the potential to also provide effective treatment options for patients with germline variants of PDGFRB. Here, we provide a summary of recurrent activating germline variants reported in PDGFRB and examine their sensitivity to different tyrosine kinase inhibitors. We show that the respective amino acid substitutions respond differently to treatment with tyrosine kinase inhibitors that correlate with previous in vivo data. Our data may assist healthcare providers when deciding personalized treatment of patients with disorders associated with activating variants in PDGFRB.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1-9"},"PeriodicalIF":4.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1038/s41431-025-01948-0
Shuxiang Goh, Tracy Dudding-Byth, Mark Pinese, Edwin P. Kirk
Many copy number variants (CNVs) are implicated in neurodevelopmental disability, but exhibit incomplete penetrance. The definition of penetrance is often unclear. In published literature, penetrance typically includes the background risk of disease, while clinicians tend to exclude risks unrelated to the genetic variant. We propose a more clinically relevant definition of penetrance and develop a new formula for this. These changes are applied to existing data sources to produce updated penetrance estimates. Our findings indicate that most CNVs studied have significantly lower penetrance than previously published. Eleven CNVs, previously described as low-penetrant, are recalculated as having a penetrance close to 0% for intellectual disability. These include 1q21.1 proximal duplications [RBM8A], 2q11.2 deletions [TMEM127], 2q13 proximal deletions and duplications [NPHP1], 6q16 duplications [SIM1], 13q12 deletions [CRYL1], 15q11.2 duplications [NIPA1, NIPA2], 15q13.3 duplications [CHRNA7], 16p12.2 duplications [CDR2], 16p13.11 duplications [MYH11] and Xp22.3 duplications [SHOX]. Previous estimates of CNV penetrance, which ranged from 10–40% have been recalculated as 1–10%. In conclusion, many previously published estimates of CNV penetrance are inflated. Re-evaluation of existing data reveals lower and more accurate penetrance estimates for intellectual disability. This has important implications for diagnosis, genetic counselling, and prenatal reporting of recurrent CNVs.
{"title":"Updated penetrance estimates for recurrent copy number variants – an improved definition and formula","authors":"Shuxiang Goh, Tracy Dudding-Byth, Mark Pinese, Edwin P. Kirk","doi":"10.1038/s41431-025-01948-0","DOIUrl":"10.1038/s41431-025-01948-0","url":null,"abstract":"Many copy number variants (CNVs) are implicated in neurodevelopmental disability, but exhibit incomplete penetrance. The definition of penetrance is often unclear. In published literature, penetrance typically includes the background risk of disease, while clinicians tend to exclude risks unrelated to the genetic variant. We propose a more clinically relevant definition of penetrance and develop a new formula for this. These changes are applied to existing data sources to produce updated penetrance estimates. Our findings indicate that most CNVs studied have significantly lower penetrance than previously published. Eleven CNVs, previously described as low-penetrant, are recalculated as having a penetrance close to 0% for intellectual disability. These include 1q21.1 proximal duplications [RBM8A], 2q11.2 deletions [TMEM127], 2q13 proximal deletions and duplications [NPHP1], 6q16 duplications [SIM1], 13q12 deletions [CRYL1], 15q11.2 duplications [NIPA1, NIPA2], 15q13.3 duplications [CHRNA7], 16p12.2 duplications [CDR2], 16p13.11 duplications [MYH11] and Xp22.3 duplications [SHOX]. Previous estimates of CNV penetrance, which ranged from 10–40% have been recalculated as 1–10%. In conclusion, many previously published estimates of CNV penetrance are inflated. Re-evaluation of existing data reveals lower and more accurate penetrance estimates for intellectual disability. This has important implications for diagnosis, genetic counselling, and prenatal reporting of recurrent CNVs.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"119-127"},"PeriodicalIF":4.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01948-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1038/s41431-025-01951-5
Jie Huang, Gary R. McLean, Andre Franke
A landmark genome-wide association study (GWAS) in 2005 led to a major discovery about the genetics of age-related macular degeneration. Since then, thousands of GWAS have been published and tens of thousands of genomic loci have been reported for association with human traits ranging from established ones (e.g. height, cardiovascular disease) to unconventional ones (e.g. same-sex sexual behavior, family income). While some claim that GWAS has already fulfilled its promises, we argue that it has yet to fully showcase its power in unraveling the secrets of the human genome and its links to phenotypes. The March 2025 bankruptcy of 23andMe serves as a stark reminder of the limited translational value of GWAS to the general public. The GWAS research community can achieve more only if we begin with a sober and objective assessment. Here, we first outline “Four Persistent Obstacles” that continue to hinder GWAS progress and discuss how a “Global Research Ecosystem” may be well-positioned to overcome them. We also highlight the transformative rise of artificial intelligence (AI) exemplified by AlphaFold’s unprecedented power in predicting protein structures. Finally, we introduce a novel concept, the “trait efficiency locus (TEL)”, as a complement to the widely used quantitative trait locus (QTL) framework, providing a new lens for evaluating genetic discoveries. One could also term it “structural trait locus (STL)”, but “TEL” emphasizes the central idea that efficiency is what ultimately matters.
{"title":"Twenty years of genome-wide association studies: Health translation challenges and AI opportunities","authors":"Jie Huang, Gary R. McLean, Andre Franke","doi":"10.1038/s41431-025-01951-5","DOIUrl":"10.1038/s41431-025-01951-5","url":null,"abstract":"A landmark genome-wide association study (GWAS) in 2005 led to a major discovery about the genetics of age-related macular degeneration. Since then, thousands of GWAS have been published and tens of thousands of genomic loci have been reported for association with human traits ranging from established ones (e.g. height, cardiovascular disease) to unconventional ones (e.g. same-sex sexual behavior, family income). While some claim that GWAS has already fulfilled its promises, we argue that it has yet to fully showcase its power in unraveling the secrets of the human genome and its links to phenotypes. The March 2025 bankruptcy of 23andMe serves as a stark reminder of the limited translational value of GWAS to the general public. The GWAS research community can achieve more only if we begin with a sober and objective assessment. Here, we first outline “Four Persistent Obstacles” that continue to hinder GWAS progress and discuss how a “Global Research Ecosystem” may be well-positioned to overcome them. We also highlight the transformative rise of artificial intelligence (AI) exemplified by AlphaFold’s unprecedented power in predicting protein structures. Finally, we introduce a novel concept, the “trait efficiency locus (TEL)”, as a complement to the widely used quantitative trait locus (QTL) framework, providing a new lens for evaluating genetic discoveries. One could also term it “structural trait locus (STL)”, but “TEL” emphasizes the central idea that efficiency is what ultimately matters.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1579-1584"},"PeriodicalIF":4.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01951-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1038/s41431-025-01930-w
Jo Balfour, Vaila Morrison, Lydia Seed, Joseph Clymer, Emma Warnants, Abigail Lampkin, Sarah M. Leiter, Gemma Chandratillake
For individuals with rare diseases, complex needs requiring multidisciplinary management can cause disjointed healthcare and challenges communicating with healthcare professionals (HCPs). ‘Patient passports’ support communication and healthcare coordination by sharing healthcare information with HCPs, reducing burden on patients/caregivers. Currently, no widely adopted passport addresses the multifaceted needs of patients with rare diseases. This pilot study was a service evaluation of a rare-disease-specific patient passport, co-designed with patients and HCPs. Patients/caregivers completed surveys before (‘pre-passport’) and after (‘post-passport’) using the passport. HCPs were surveyed on their perception of the passport. Of 157 ‘pre-passport’ survey respondents, 96.2% spent considerable time explaining medical needs to new care teams; 65.6% found communicating care needs challenging. Nearly all respondents (99.4%) believed a document presenting relevant healthcare information would be helpful. Among 55 ‘post-passport’ survey respondents, 85.1% used the passport during care interactions; 72.2% found it eased communication with unfamiliar teams, and 64.2% felt more confident communicating their needs. Over half (53.8%) felt the passport helped access needed care, 67.9% found it more useful than existing tools, and 75.9% were highly likely to recommend it to peers. All 31 HCP respondents listed perceived benefits, including improved HCP-patient/caregiver communication; some noted a preference for formal endorsement. By alleviating patient/caregiver-HCP communication challenges, this rare-disease-specific patient passport can enhance healthcare coordination and patient experiences. Participants’ use of the passport during interactions with care teams and likelihood of recommendation to peers support its widespread integration. Further work to assess usability across healthcare settings and to gain formal endorsement is warranted.
{"title":"Patient passports for rare diseases: results of a pilot study","authors":"Jo Balfour, Vaila Morrison, Lydia Seed, Joseph Clymer, Emma Warnants, Abigail Lampkin, Sarah M. Leiter, Gemma Chandratillake","doi":"10.1038/s41431-025-01930-w","DOIUrl":"10.1038/s41431-025-01930-w","url":null,"abstract":"For individuals with rare diseases, complex needs requiring multidisciplinary management can cause disjointed healthcare and challenges communicating with healthcare professionals (HCPs). ‘Patient passports’ support communication and healthcare coordination by sharing healthcare information with HCPs, reducing burden on patients/caregivers. Currently, no widely adopted passport addresses the multifaceted needs of patients with rare diseases. This pilot study was a service evaluation of a rare-disease-specific patient passport, co-designed with patients and HCPs. Patients/caregivers completed surveys before (‘pre-passport’) and after (‘post-passport’) using the passport. HCPs were surveyed on their perception of the passport. Of 157 ‘pre-passport’ survey respondents, 96.2% spent considerable time explaining medical needs to new care teams; 65.6% found communicating care needs challenging. Nearly all respondents (99.4%) believed a document presenting relevant healthcare information would be helpful. Among 55 ‘post-passport’ survey respondents, 85.1% used the passport during care interactions; 72.2% found it eased communication with unfamiliar teams, and 64.2% felt more confident communicating their needs. Over half (53.8%) felt the passport helped access needed care, 67.9% found it more useful than existing tools, and 75.9% were highly likely to recommend it to peers. All 31 HCP respondents listed perceived benefits, including improved HCP-patient/caregiver communication; some noted a preference for formal endorsement. By alleviating patient/caregiver-HCP communication challenges, this rare-disease-specific patient passport can enhance healthcare coordination and patient experiences. Participants’ use of the passport during interactions with care teams and likelihood of recommendation to peers support its widespread integration. Further work to assess usability across healthcare settings and to gain formal endorsement is warranted.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"99-107"},"PeriodicalIF":4.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01930-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1038/s41431-025-01954-2
Joanne Scarfe, Alexis Turner, Christian Meagher, Michelle A Farrar, Kaustuv Bhattacharya, Sarah-Grace Paguinto, Nicole Millis, Jo Watson, Didu S Kariyawasam, Sarah Norris
The future use of genomics in Australia's newborn bloodspot screening (NBS) program is likely to be associated with both positive and negative impacts. Before adopting this technology, it is important to understand the views of all stakeholders, including scientists, health care professionals (HCPs) and policy-makers involved in delivering the program. Semi-structured interviews or small group discussions were undertaken with 19 HCPs or scientists, and 16 policy-makers. Responses were analyzed using inductive content analysis. Participants acknowledged the potential of genomics in NBS to improve early detection, diagnosis, and treatment. However, they more often highlighted potential risks of genomics in NBS, and the broader technical and implementation challenges to the health system. Perspectives varied on whether genomic NBS should align with Australia's current NBS paradigm, focusing on severe, treatable, early-onset conditions, or whether wider potential uses of genomic NBS data (such as later clinical uses) should drive a 'paradigm shift' in policy that values benefits beyond newborn screening. Respondents reported that effective implementation of genomic NBS will require adequate health system readiness, which will require national program coordination, adequate consent, an agreed ethical approach to reporting uncertain or non-actionable results, enhanced workforce capacity, enhanced laboratory and data infrastructure, equitable access to downstream health services, and ethically and legally agreed uses of the genomic data. Findings offer insights for Australia and other countries considering the use of genomics in NBS programs.
{"title":"\"Jumping too far ahead\": Australian healthcare professional, scientist, and policy maker perspectives on using genomics in newborn screening.","authors":"Joanne Scarfe, Alexis Turner, Christian Meagher, Michelle A Farrar, Kaustuv Bhattacharya, Sarah-Grace Paguinto, Nicole Millis, Jo Watson, Didu S Kariyawasam, Sarah Norris","doi":"10.1038/s41431-025-01954-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01954-2","url":null,"abstract":"<p><p>The future use of genomics in Australia's newborn bloodspot screening (NBS) program is likely to be associated with both positive and negative impacts. Before adopting this technology, it is important to understand the views of all stakeholders, including scientists, health care professionals (HCPs) and policy-makers involved in delivering the program. Semi-structured interviews or small group discussions were undertaken with 19 HCPs or scientists, and 16 policy-makers. Responses were analyzed using inductive content analysis. Participants acknowledged the potential of genomics in NBS to improve early detection, diagnosis, and treatment. However, they more often highlighted potential risks of genomics in NBS, and the broader technical and implementation challenges to the health system. Perspectives varied on whether genomic NBS should align with Australia's current NBS paradigm, focusing on severe, treatable, early-onset conditions, or whether wider potential uses of genomic NBS data (such as later clinical uses) should drive a 'paradigm shift' in policy that values benefits beyond newborn screening. Respondents reported that effective implementation of genomic NBS will require adequate health system readiness, which will require national program coordination, adequate consent, an agreed ethical approach to reporting uncertain or non-actionable results, enhanced workforce capacity, enhanced laboratory and data infrastructure, equitable access to downstream health services, and ethically and legally agreed uses of the genomic data. Findings offer insights for Australia and other countries considering the use of genomics in NBS programs.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1038/s41431-025-01947-1
Karen J Low, Julia Foreman, Rachel J Hobson, Hannah Kwuo, Elena Martinez-Cayuelas, Berta Almoguera, Purin Marin-Reina, Stefano G Caraffi, Livia Garavelli, Emily Woods, Meena Balasubramanian, Allan Bayat, Charlotte W Ockeloen, Caroline M Wright, Helen V Firth, Tim J Cole
Children with monogenic neurodevelopmental disorders often grow abnormally. Gene-specific growth charts would be useful but require large samples to construct them using the conventional LMS method. We transformed anthropometry to British 1990 reference z-scores for 328 UK and 264 international individuals with ANKRD11, ARID1B, ASXL3, DDX3X, KMT2A, or SATB2-related disorders, and modelled mean and standard deviation (SD) of the z-scores as gene-specific linear age trends adjusted for sex. Assuming the same skewness in the reference and rare disease distributions, we then back-transformed the mean ±2 SD lines to give gene-specific median, 2nd, and 98th centiles. The resulting z-score charts look plausible on several counts. Only KMT2A shows a (rising) age trend in median height, while BMI and weight increase for several genes, possibly reflecting population trends. Apart from SATB2 and DDX3X, the gene-specific medians are all below the reference (range 0.1th centile for height KMT2A to 36th centile for BMI ANKRD11). Median OFC z-score shows no age trend, with medians ranging from 10th to 30th centile, and ASXL3 is lowest, on the 3rd centile. In 19/24 cases, the centiles for the two sexes are the same on the z-score scale. Our LMSz method produces gene-specific growth charts for rare diseases, which, when used in the correct context, could be an important clinical tool. We plan to automate it within the DECIPHER platform, enabling availability for relevant genes.
{"title":"The LMSz method - an automatable scalable approach to constructing gene-specific growth charts in rare disorders.","authors":"Karen J Low, Julia Foreman, Rachel J Hobson, Hannah Kwuo, Elena Martinez-Cayuelas, Berta Almoguera, Purin Marin-Reina, Stefano G Caraffi, Livia Garavelli, Emily Woods, Meena Balasubramanian, Allan Bayat, Charlotte W Ockeloen, Caroline M Wright, Helen V Firth, Tim J Cole","doi":"10.1038/s41431-025-01947-1","DOIUrl":"10.1038/s41431-025-01947-1","url":null,"abstract":"<p><p>Children with monogenic neurodevelopmental disorders often grow abnormally. Gene-specific growth charts would be useful but require large samples to construct them using the conventional LMS method. We transformed anthropometry to British 1990 reference z-scores for 328 UK and 264 international individuals with ANKRD11, ARID1B, ASXL3, DDX3X, KMT2A, or SATB2-related disorders, and modelled mean and standard deviation (SD) of the z-scores as gene-specific linear age trends adjusted for sex. Assuming the same skewness in the reference and rare disease distributions, we then back-transformed the mean ±2 SD lines to give gene-specific median, 2nd, and 98th centiles. The resulting z-score charts look plausible on several counts. Only KMT2A shows a (rising) age trend in median height, while BMI and weight increase for several genes, possibly reflecting population trends. Apart from SATB2 and DDX3X, the gene-specific medians are all below the reference (range 0.1th centile for height KMT2A to 36th centile for BMI ANKRD11). Median OFC z-score shows no age trend, with medians ranging from 10th to 30th centile, and ASXL3 is lowest, on the 3rd centile. In 19/24 cases, the centiles for the two sexes are the same on the z-score scale. Our LMSz method produces gene-specific growth charts for rare diseases, which, when used in the correct context, could be an important clinical tool. We plan to automate it within the DECIPHER platform, enabling availability for relevant genes.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：