Pub Date : 2025-10-27DOI: 10.1038/s41431-025-01965-z
Mert Karakaya, Iman Ragab, Vera Riehmer, Florian Erger, Nihal Hussien Aly, Seung Woo Ryu, Go Hun Seo, Marc Hoemberg, Anne Maria Schultheis, Christian Netzer, Boris Decarolis
{"title":"Correction: ELMO2-related intraosseous vascular malformation: new cases with novel pathogenic variants, clinical follow-up and therapeutic approaches.","authors":"Mert Karakaya, Iman Ragab, Vera Riehmer, Florian Erger, Nihal Hussien Aly, Seung Woo Ryu, Go Hun Seo, Marc Hoemberg, Anne Maria Schultheis, Christian Netzer, Boris Decarolis","doi":"10.1038/s41431-025-01965-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01965-z","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376645","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 : 2025-10-27DOI: 10.1038/s41431-025-01966-y
Melek Firat Altay, Anne Gregor, Dominique Braun, Claudine Rieubland, Matthias Gautschi, Eveline Perret Hoigné, Rike Schiller, Boris Keren, Alejandra Afenjar, Undiagnosed Diseases Network, Julian A. Martinez-Agosto, Jill A. Rosenfeld, Christiane Zweier
Serine/arginine repetitive matrix protein 1 (SRRM1) is a key component of spliceosomes and plays various roles in messenger RNA processing. To date, its function in the nervous system has not been elucidated, and germline variants in SRRM1 have not yet been implicated in disease. Through international collaboration, we have identified three individuals harbouring heterozygous truncating variants in SRRM1, presenting variably with developmental delay, intellectual disability, short stature, behavioural and skeletal anomalies, and facial dysmorphism. Two of the variants occurred de novo, while the third could not be tested in the parents. Reduction of SRRM1 to 50% in SKNBE2 cells by introducing a truncating variant via CRISPR-Cas9 editing, followed by differentiation into neuron-like cells, resulted in impaired cell proliferation, migration, and neurite outgrowth compared to wild-type cells. Additionally, the role of SRRM1 in nervous system development and functioning was investigated in vivo using a Drosophila model. Pan-neuronal knockdown of the orthologue Srrm1 led to reduced viability, while motoneuronal knockdown impaired gross neurological function. Taken together, we provide multiple lines of evidence that loss of SRRM1 is associated with nervous system-related phenotypes, and that its haploinsufficiency may be causative for a neurodevelopmental disorder.
{"title":"Heterozygous loss of SRRM1 may be associated with neurodevelopmental phenotypes and anomalies in cell growth and neurite morphology","authors":"Melek Firat Altay, Anne Gregor, Dominique Braun, Claudine Rieubland, Matthias Gautschi, Eveline Perret Hoigné, Rike Schiller, Boris Keren, Alejandra Afenjar, Undiagnosed Diseases Network, Julian A. Martinez-Agosto, Jill A. Rosenfeld, Christiane Zweier","doi":"10.1038/s41431-025-01966-y","DOIUrl":"10.1038/s41431-025-01966-y","url":null,"abstract":"Serine/arginine repetitive matrix protein 1 (SRRM1) is a key component of spliceosomes and plays various roles in messenger RNA processing. To date, its function in the nervous system has not been elucidated, and germline variants in SRRM1 have not yet been implicated in disease. Through international collaboration, we have identified three individuals harbouring heterozygous truncating variants in SRRM1, presenting variably with developmental delay, intellectual disability, short stature, behavioural and skeletal anomalies, and facial dysmorphism. Two of the variants occurred de novo, while the third could not be tested in the parents. Reduction of SRRM1 to 50% in SKNBE2 cells by introducing a truncating variant via CRISPR-Cas9 editing, followed by differentiation into neuron-like cells, resulted in impaired cell proliferation, migration, and neurite outgrowth compared to wild-type cells. Additionally, the role of SRRM1 in nervous system development and functioning was investigated in vivo using a Drosophila model. Pan-neuronal knockdown of the orthologue Srrm1 led to reduced viability, while motoneuronal knockdown impaired gross neurological function. Taken together, we provide multiple lines of evidence that loss of SRRM1 is associated with nervous system-related phenotypes, and that its haploinsufficiency may be causative for a neurodevelopmental disorder.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"201-208"},"PeriodicalIF":4.6,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01966-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376626","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 : 2025-10-26DOI: 10.1038/s41431-025-01969-9
Marco Tartaglia, Andrea Ciolfi
{"title":"To sign or not to sign: Is this still the question?","authors":"Marco Tartaglia, Andrea Ciolfi","doi":"10.1038/s41431-025-01969-9","DOIUrl":"10.1038/s41431-025-01969-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"169-170"},"PeriodicalIF":4.6,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145372507","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 : 2025-10-24DOI: 10.1038/s41431-025-01963-1
Jaison Jeevan Sequeira, Swathy Krishna M, George van Driem, Mohammed S Mustak, Ranajit Das
Research has shown that the present-day population on the Indian subcontinent derives its ancestry from at least three components identified with pre-Indo-Iranian agriculturalists once inhabiting the Iranian plateau, pastoralists originating from the Pontic-Caspian steppe and ancient hunter-gatherer related to the Andamanese Islanders. The present-day Indian gene pool represents a gradient of mixtures from these three sources. However, with more sequences of ancient and modern genomes and fine structure analyses, we can expect a more complex picture of ancestry to emerge. Focusing on Dravidian linguistic groups, this study proposes a fourth putative source potentially branching from the basal Middle Eastern component that contributed to the Iranian plateau farmer related ancestry. The Elamo-Dravidian theory and the linguistic phylogeny of the Dravidian family tree provide chronological fits for the genetic findings presented here. Our findings show a correlation between the linguistic and genetic lineages in language communities speaking Dravidian languages when they are modelled together. We suggest that this source we identified in the Koraga tribe, which we shall call 'Proto-Dravidian' ancestry, emerged around the dawn of the Indus Valley civilisation. This ancestry is distinct from all other sources described so far, and its plausible origin not later than 4400 years ago on the region between the Iranian plateau and the Indus valley supports a Dravidian heartland before the arrival of Indo-European languages on the Indian subcontinent. Admixture analysis shows that this Proto-Dravidian ancestry is still carried by most modern inhabitants of the Indian subcontinent other than the tribal populations.
{"title":"Novel 4400-year-old ancestral component in a tribe speaking a Dravidian language.","authors":"Jaison Jeevan Sequeira, Swathy Krishna M, George van Driem, Mohammed S Mustak, Ranajit Das","doi":"10.1038/s41431-025-01963-1","DOIUrl":"10.1038/s41431-025-01963-1","url":null,"abstract":"<p><p>Research has shown that the present-day population on the Indian subcontinent derives its ancestry from at least three components identified with pre-Indo-Iranian agriculturalists once inhabiting the Iranian plateau, pastoralists originating from the Pontic-Caspian steppe and ancient hunter-gatherer related to the Andamanese Islanders. The present-day Indian gene pool represents a gradient of mixtures from these three sources. However, with more sequences of ancient and modern genomes and fine structure analyses, we can expect a more complex picture of ancestry to emerge. Focusing on Dravidian linguistic groups, this study proposes a fourth putative source potentially branching from the basal Middle Eastern component that contributed to the Iranian plateau farmer related ancestry. The Elamo-Dravidian theory and the linguistic phylogeny of the Dravidian family tree provide chronological fits for the genetic findings presented here. Our findings show a correlation between the linguistic and genetic lineages in language communities speaking Dravidian languages when they are modelled together. We suggest that this source we identified in the Koraga tribe, which we shall call 'Proto-Dravidian' ancestry, emerged around the dawn of the Indus Valley civilisation. This ancestry is distinct from all other sources described so far, and its plausible origin not later than 4400 years ago on the region between the Iranian plateau and the Indus valley supports a Dravidian heartland before the arrival of Indo-European languages on the Indian subcontinent. Admixture analysis shows that this Proto-Dravidian ancestry is still carried by most modern inhabitants of the Indian subcontinent other than the tribal populations.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367766","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 : 2025-10-23DOI: 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.
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