Pub Date : 2026-01-13DOI: 10.1038/s41431-025-01993-9
Halianna Van Niel, Mariana Lauretta, Emma Baker, Lorraine O'Donnell, Charlotte Boulton, Celia Brenchley, David Coman, Evyenia Michellis, Himanshu Goel, Geoff Thompson, Richard Webster, Georgia Paxton, Zornitza Stark, Ingrid E Scheffer, Michael S Hildebrand, David J Amor, Angela T Morgan
The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, however, no studies have examined genetic diagnostic yield for childhood apraxia of speech (CAS) and dysarthria in a clinical setting. Here, we used a clinically accredited genomics pipeline to investigate genetic diagnostic yield and variables predictive of a genetic diagnosis in a tertiary hospital speech clinic. A cohort of 153 children (range 2;7-16;5 years, 42 female) ascertained for motor speech disorder were assessed by a clinical geneticist and speech pathologist and underwent chromosomal microarray, Fragile X and exome sequencing. Odds ratios identified predictors of genetic diagnosis. 44/153 (29%, 15 female) had pathogenic variants (30 de novo), encompassing monogenic conditions (n = 35) and copy number variants (n = 9) across 38 distinct disorders. Delayed walking, fine and gross motor disorder, receptive language impairment and/or cognitive impairment, and dysmorphism were associated with a genetic diagnosis. The presence of CAS and dysarthria was more commonly associated with a genetic diagnosis than CAS alone. Autism spectrum disorder was less commonly associated with a genetic diagnosis. No child had a Fragile X diagnosis. The clinical genetic diagnostic yield for motor speech disorders is comparable to epilepsy and cerebral palsy, conditions where genetic testing is routine in most centres, unlike for motor speech disorders. Children with motor speech disorder with co-occurring motor, language and/or learning deficits, should be prioritised for genomic testing.
{"title":"Childhood motor speech disorders: who to prioritise for genetic testing.","authors":"Halianna Van Niel, Mariana Lauretta, Emma Baker, Lorraine O'Donnell, Charlotte Boulton, Celia Brenchley, David Coman, Evyenia Michellis, Himanshu Goel, Geoff Thompson, Richard Webster, Georgia Paxton, Zornitza Stark, Ingrid E Scheffer, Michael S Hildebrand, David J Amor, Angela T Morgan","doi":"10.1038/s41431-025-01993-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01993-9","url":null,"abstract":"<p><p>The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, however, no studies have examined genetic diagnostic yield for childhood apraxia of speech (CAS) and dysarthria in a clinical setting. Here, we used a clinically accredited genomics pipeline to investigate genetic diagnostic yield and variables predictive of a genetic diagnosis in a tertiary hospital speech clinic. A cohort of 153 children (range 2;7-16;5 years, 42 female) ascertained for motor speech disorder were assessed by a clinical geneticist and speech pathologist and underwent chromosomal microarray, Fragile X and exome sequencing. Odds ratios identified predictors of genetic diagnosis. 44/153 (29%, 15 female) had pathogenic variants (30 de novo), encompassing monogenic conditions (n = 35) and copy number variants (n = 9) across 38 distinct disorders. Delayed walking, fine and gross motor disorder, receptive language impairment and/or cognitive impairment, and dysmorphism were associated with a genetic diagnosis. The presence of CAS and dysarthria was more commonly associated with a genetic diagnosis than CAS alone. Autism spectrum disorder was less commonly associated with a genetic diagnosis. No child had a Fragile X diagnosis. The clinical genetic diagnostic yield for motor speech disorders is comparable to epilepsy and cerebral palsy, conditions where genetic testing is routine in most centres, unlike for motor speech disorders. Children with motor speech disorder with co-occurring motor, language and/or learning deficits, should be prioritised for genomic testing.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965725","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 : 2026-01-12DOI: 10.1038/s41431-025-02008-3
Kristian Kleine Schaars, Marga Nijenhuis, Bianca Soree, Nienke J. de Boer-Veger, Anne-Marie Buunk, Henk-Jan Guchelaar, Elisa J. F. Houwink, Arne Risselada, Gerard A. P. J. M. Rongen, Ron H. N. van Schaik, Jesse J. Swen, Daan Touw, Vera H. M. Deneer, Roos van Westrhenen
The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene–drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being “potentially beneficial”. Genotyping prior to treatment can be considered on an individual patient basis.
{"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction between CYP2D6 and CYP2C19 and tricyclic antidepressants","authors":"Kristian Kleine Schaars, Marga Nijenhuis, Bianca Soree, Nienke J. de Boer-Veger, Anne-Marie Buunk, Henk-Jan Guchelaar, Elisa J. F. Houwink, Arne Risselada, Gerard A. P. J. M. Rongen, Ron H. N. van Schaik, Jesse J. Swen, Daan Touw, Vera H. M. Deneer, Roos van Westrhenen","doi":"10.1038/s41431-025-02008-3","DOIUrl":"10.1038/s41431-025-02008-3","url":null,"abstract":"The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene–drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being “potentially beneficial”. Genotyping prior to treatment can be considered on an individual patient basis.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 3","pages":"379-386"},"PeriodicalIF":4.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-02008-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959135","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 : 2026-01-10DOI: 10.1038/s41431-025-02009-2
Yasmin Bylstra, Weng Khong Lim, Jing Xian Teo, Melody Menezes, Jan Hodgson, Fabian Yap, John C. Chambers, Khung Keong Yeo, Patrick Tan, David J. Amor, Saumya S. Jamuar
The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.
{"title":"Unexpected genotypes associated with severe paediatric conditions identified in a healthy population cohort","authors":"Yasmin Bylstra, Weng Khong Lim, Jing Xian Teo, Melody Menezes, Jan Hodgson, Fabian Yap, John C. Chambers, Khung Keong Yeo, Patrick Tan, David J. Amor, Saumya S. Jamuar","doi":"10.1038/s41431-025-02009-2","DOIUrl":"10.1038/s41431-025-02009-2","url":null,"abstract":"The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 3","pages":"368-378"},"PeriodicalIF":4.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948297","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 : 2026-01-10DOI: 10.1038/s41431-025-02012-7
Michael P. Mackley, Megan A. Dickson, Anna Szuto, James Anderson, David Chitayat, Robin Z. Hayeems, Roberto Mendoza-Londono, Eugene Ng, Martin Offringa, Yi Wen Wang, Linh G. Ly, Lauren Chad
Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnostic yield and potential to influence treatment and care planning decisions, little is known about how families experience rGS in the ICU and the emotional and contextual factors influencing their testing-related decisions. We conducted semi-structured interviews with twenty-three parents of infants who consented to rGS in an ICU at two tertiary hospitals in Toronto, Ontario, Canada; all interviews took place in close proximity to the decision to pursue rGS. Parents’ experiences with rGS and the related genetics consultation demonstrated a complex interplay of emotional, pragmatic, relational, and temporal ‘sense-making’ to grasp what was happening. Overall, parents felt overwhelmed in the ICU. Some de-prioritized genetic testing compared to other aspects of care while others reflected negatively or ambivalently on rGS or felt that it was implicitly expected that they pursue it. We conclude that an rGS approach tailored to the ICU setting is needed. Consideration should be given to distributing complex decisions (such as those relating to primary vs. secondary findings) across multiple briefer visits, and alleviating decisional burden by reframing rGS as one of the many shared decisions made with families in this setting.
{"title":"Experiencing acute genomic care: perspectives from parents in the neonatal and paediatric intensive care units towards rapid genomic sequencing","authors":"Michael P. Mackley, Megan A. Dickson, Anna Szuto, James Anderson, David Chitayat, Robin Z. Hayeems, Roberto Mendoza-Londono, Eugene Ng, Martin Offringa, Yi Wen Wang, Linh G. Ly, Lauren Chad","doi":"10.1038/s41431-025-02012-7","DOIUrl":"10.1038/s41431-025-02012-7","url":null,"abstract":"Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnostic yield and potential to influence treatment and care planning decisions, little is known about how families experience rGS in the ICU and the emotional and contextual factors influencing their testing-related decisions. We conducted semi-structured interviews with twenty-three parents of infants who consented to rGS in an ICU at two tertiary hospitals in Toronto, Ontario, Canada; all interviews took place in close proximity to the decision to pursue rGS. Parents’ experiences with rGS and the related genetics consultation demonstrated a complex interplay of emotional, pragmatic, relational, and temporal ‘sense-making’ to grasp what was happening. Overall, parents felt overwhelmed in the ICU. Some de-prioritized genetic testing compared to other aspects of care while others reflected negatively or ambivalently on rGS or felt that it was implicitly expected that they pursue it. We conclude that an rGS approach tailored to the ICU setting is needed. Consideration should be given to distributing complex decisions (such as those relating to primary vs. secondary findings) across multiple briefer visits, and alleviating decisional burden by reframing rGS as one of the many shared decisions made with families in this setting.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 3","pages":"387-394"},"PeriodicalIF":4.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948330","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 : 2026-01-09DOI: 10.1038/s41431-025-01998-4
George van Driem, Jaison Jeevan Sequeira, Swathy Krishna, Mohammed Shafiul Mustak, Ranajit Das
{"title":"Chronological frameworks for Indo-European languages: Insights from linguistics, archaeology and genomics.","authors":"George van Driem, Jaison Jeevan Sequeira, Swathy Krishna, Mohammed Shafiul Mustak, Ranajit Das","doi":"10.1038/s41431-025-01998-4","DOIUrl":"10.1038/s41431-025-01998-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145943001","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 : 2026-01-08DOI: 10.1038/s41431-025-01997-5
Ramakrishnan Sitaraman
{"title":"The absolute chronology of the presence of Indo-European/Indic languages in the Indian subcontinent.","authors":"Ramakrishnan Sitaraman","doi":"10.1038/s41431-025-01997-5","DOIUrl":"10.1038/s41431-025-01997-5","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932979","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 : 2026-01-08DOI: 10.1038/s41431-025-01999-3
Eleanor Roberts, Nicola Flaum, D Gareth Evans
{"title":"Clinical implementation of polygenic risk scores.","authors":"Eleanor Roberts, Nicola Flaum, D Gareth Evans","doi":"10.1038/s41431-025-01999-3","DOIUrl":"https://doi.org/10.1038/s41431-025-01999-3","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932940","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 : 2026-01-08DOI: 10.1038/s41431-025-02002-9
Andrea Gazzin, Marta Calvo, Federico Rondot, Giuseppe Reynolds, Chiara Leoni, Marcello Niceta, Maria Lisa Dentici, Maria Cristina Digilio, Francesca Lepri, Emanuele Monda, Ilaria Carelli, Eva Trevisson, Iris Scala, Giorgia Mancano, Elena Andreucci, Franco Stanzial, Francesco Brancati, Giuseppe Zampino, Luigi Tarani, Roberto Paparella, Diana Carli, Anna Maria Villar, Elena Banaudi, Stefania Massuras, Simona Cardaropoli, Paola Daniele, Elena Airulo, Chiara Riggi, Giulio Calcagni, Giovanni Battista Ferrero, Giuseppe Limongelli, Alessandro De Luca, Marco Tartaglia, Alessandro Mussa
Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases from a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.
{"title":"Domain-specific phenotypic profiles in RAF1-related Noonan syndrome","authors":"Andrea Gazzin, Marta Calvo, Federico Rondot, Giuseppe Reynolds, Chiara Leoni, Marcello Niceta, Maria Lisa Dentici, Maria Cristina Digilio, Francesca Lepri, Emanuele Monda, Ilaria Carelli, Eva Trevisson, Iris Scala, Giorgia Mancano, Elena Andreucci, Franco Stanzial, Francesco Brancati, Giuseppe Zampino, Luigi Tarani, Roberto Paparella, Diana Carli, Anna Maria Villar, Elena Banaudi, Stefania Massuras, Simona Cardaropoli, Paola Daniele, Elena Airulo, Chiara Riggi, Giulio Calcagni, Giovanni Battista Ferrero, Giuseppe Limongelli, Alessandro De Luca, Marco Tartaglia, Alessandro Mussa","doi":"10.1038/s41431-025-02002-9","DOIUrl":"10.1038/s41431-025-02002-9","url":null,"abstract":"Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases from a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"209-215"},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932932","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 : 2026-01-08DOI: 10.1038/s41431-025-02006-5
Roseline Vibert, Yahya El Baroudi, Maude Vecten, Alexandre Buffet, Virginie Verkarre, Anne-Paule Gimenez-Roqueplo, Stéphane Richard, Judith Favier, Anne Barlier, Sophie Giraud, Nelly Burnichon
Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene panels (MGP) to characterize RCC linked to hereditary syndromes. The current French guidelines of the national reference network for hereditary renal cancers (PREDIR) recommend genetic testing for patients meeting specific clinical criteria. This study evaluates the diagnostic yield and the relevance of current criteria, the utility of MGP testing, and the added value of tumor analyses. We retrospectively analyzed 2057 RCC patients who underwent germline MGP testing across three French hospital laboratories. Tumor analysis results from 140 patients were also evaluated. The overall rate of germline pathogenic/likely pathogenic variants was 3.5%, with 39% in syndromic cases and 1.2% in apparently sporadic cases. Tumor analyses identified somatic pathogenic variants in 56.3% of cases. Our data support that the likelihood of identifying a germline PV is low in patients with sporadic single clear cell RCC, and that the clinical utility of testing all patients with other sporadic subtypes appears limited. This suggests a need to revise current testing criteria in patients with sporadic single RCC, for example, by lowering the age threshold for genetic testing from 45 to 40 years in clear cell RCC, and to 50 years in other subtypes. We also suggest incorporating tumor analyses to distinguish hereditary RCC from sporadic cases driven by tumor-specific pathogenic variants.
{"title":"Insights from 2057 germline genetic tests in renal cell carcinoma patients support revisiting testing criteria","authors":"Roseline Vibert, Yahya El Baroudi, Maude Vecten, Alexandre Buffet, Virginie Verkarre, Anne-Paule Gimenez-Roqueplo, Stéphane Richard, Judith Favier, Anne Barlier, Sophie Giraud, Nelly Burnichon","doi":"10.1038/s41431-025-02006-5","DOIUrl":"10.1038/s41431-025-02006-5","url":null,"abstract":"Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene panels (MGP) to characterize RCC linked to hereditary syndromes. The current French guidelines of the national reference network for hereditary renal cancers (PREDIR) recommend genetic testing for patients meeting specific clinical criteria. This study evaluates the diagnostic yield and the relevance of current criteria, the utility of MGP testing, and the added value of tumor analyses. We retrospectively analyzed 2057 RCC patients who underwent germline MGP testing across three French hospital laboratories. Tumor analysis results from 140 patients were also evaluated. The overall rate of germline pathogenic/likely pathogenic variants was 3.5%, with 39% in syndromic cases and 1.2% in apparently sporadic cases. Tumor analyses identified somatic pathogenic variants in 56.3% of cases. Our data support that the likelihood of identifying a germline PV is low in patients with sporadic single clear cell RCC, and that the clinical utility of testing all patients with other sporadic subtypes appears limited. This suggests a need to revise current testing criteria in patients with sporadic single RCC, for example, by lowering the age threshold for genetic testing from 45 to 40 years in clear cell RCC, and to 50 years in other subtypes. We also suggest incorporating tumor analyses to distinguish hereditary RCC from sporadic cases driven by tumor-specific pathogenic variants.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 3","pages":"421-428"},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932880","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 : 2026-01-08DOI: 10.1038/s41431-025-02001-w
Valentina Muto, Giulia Fasano, Francesca Clementina Radio, Catia Pedalino, Mattia Carvetta, Simona Coppola, Erika Zara, Stefania Petrini, Caroline Schluth-Bolard, Claire Bilbault, Salima El Chehadeh, Bénédicte Gérard, Anne de Saint-Martin, Daniel C. Koboldt, Emily Sites, Cynthia Curry, Theresia Herget, Ann-Sophie Höing, Leonie von Elsner, Eileen Elizabeth Barr, Ugur Hodoglugil, Anne Slavotinek, Marco Tartaglia, Antonella Lauri
We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects. In vitro and in vivo analyses documented impaired Golgi integrity, vesicle trafficking, and brain and body axes development. Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants. Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology. Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients’ microcephaly. These findings expand the ARF3-related Golgipathy mutational spectrum, strengthen previous observations linking variants with dominant negative behavior to a markedly severe phenotype, and underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction.
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