Pub Date : 2025-09-29DOI: 10.1038/s41431-025-01944-4
Asier Iturrate, Nurit Assia Batzir, Ranit Jaron, David Garcia-Valentin, Julian Nevado, Jair Tenorio-Castano, Pablo Lapunzina, Kamila Lee, Rotem Greenberg, Dvora Sassi, Sharon Aharoni, Alla Kuzminsky, Lina Basel-Salmon, Naama Orenstein, Yakov Fellig, Shay Ben-Shachar, Dina Marek-Yagel, Victor L Ruiz-Perez
Excitation-contraction (EC) coupling is an essential process for skeletal muscle function. Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of CACNB1 in the affected individuals from each family. CACNB1 encodes the β1 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca2+ channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all CACNB1 transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified CACNB1 variants was further validated by replicating one of them (c.85-1G>A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of β1 subunits, these cells displayed severely reduced protein levels of α1S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in CACNB1 cause a new congenital muscular disorder.
{"title":"N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder.","authors":"Asier Iturrate, Nurit Assia Batzir, Ranit Jaron, David Garcia-Valentin, Julian Nevado, Jair Tenorio-Castano, Pablo Lapunzina, Kamila Lee, Rotem Greenberg, Dvora Sassi, Sharon Aharoni, Alla Kuzminsky, Lina Basel-Salmon, Naama Orenstein, Yakov Fellig, Shay Ben-Shachar, Dina Marek-Yagel, Victor L Ruiz-Perez","doi":"10.1038/s41431-025-01944-4","DOIUrl":"10.1038/s41431-025-01944-4","url":null,"abstract":"<p><p>Excitation-contraction (EC) coupling is an essential process for skeletal muscle function. Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of CACNB1 in the affected individuals from each family. CACNB1 encodes the β1 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca<sup>2+</sup> channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all CACNB1 transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified CACNB1 variants was further validated by replicating one of them (c.85-1G>A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of β1 subunits, these cells displayed severely reduced protein levels of α1S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in CACNB1 cause a new congenital muscular disorder.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190927","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 : 2025-09-27DOI: 10.1038/s41431-025-01957-z
Morag A. Lewis, Bradley A. Schulte, Judy R. Dubno, Karen P. Steel
Age-related hearing loss (ARHL) is a common, complex disease with high heritability, but its underlying genetic landscape remains unclear. Studying such a condition requires large cohorts, detailed genotyping, and deep phenotyping. However, while large cohorts with next-generation sequence data are becoming increasingly common, the challenge of administering audiometric tests at scale has meant that in-depth auditory phenotyping is rarely included. Here we present our analyses of three cohorts with different forms of phenotype data, which reveal the differences made by even small changes in phenotyping. Detailed audiometry enables interrogation of genetic data by auditory phenotypes, but if these data are not available, self-reports of hearing difficulty may also serve. However, relying on medical records alone is ineffective for classifying biobank participants for a common condition like ARHL, and is likely to result in many people being wrongly classified in the control group.
{"title":"The importance of accurate phenotyping in large-scale analyses of common disorders such as hearing loss","authors":"Morag A. Lewis, Bradley A. Schulte, Judy R. Dubno, Karen P. Steel","doi":"10.1038/s41431-025-01957-z","DOIUrl":"10.1038/s41431-025-01957-z","url":null,"abstract":"Age-related hearing loss (ARHL) is a common, complex disease with high heritability, but its underlying genetic landscape remains unclear. Studying such a condition requires large cohorts, detailed genotyping, and deep phenotyping. However, while large cohorts with next-generation sequence data are becoming increasingly common, the challenge of administering audiometric tests at scale has meant that in-depth auditory phenotyping is rarely included. Here we present our analyses of three cohorts with different forms of phenotype data, which reveal the differences made by even small changes in phenotyping. Detailed audiometry enables interrogation of genetic data by auditory phenotypes, but if these data are not available, self-reports of hearing difficulty may also serve. However, relying on medical records alone is ineffective for classifying biobank participants for a common condition like ARHL, and is likely to result in many people being wrongly classified in the control group.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1708-1711"},"PeriodicalIF":4.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01957-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181762","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 : 2025-09-27DOI: 10.1038/s41431-025-01953-3
Gráinne Butler, David J. Amor, Catherine Quinlan
Reproductive genetic carrier screening (RGCS) is expanding in both public and private healthcare. The primary aim is to identify carrier status for genetic disorders, inform reproductive decision making and promote reproductive autonomy. As screening panels have increased, the potential for findings with personal health implications rises. We report the prevalence of COL4A3/COL4A4 heterozygous variants within a population undergoing RGCS in a private setting and propose a comprehensive management plan for the ongoing care of this patient cohort. Acknowledging that comprehensive guidelines exist for genetic testing and management of Alport syndrome as a broad patient group, this communication seeks to highlight the increasingly common finding of autosomal dominant Alport syndrome and proposes accessible and practical strategies for the clinicians encountering these patients.
{"title":"From screening to strategy: Clinical implications of COL4A3/COL4A4 variants found in reproductive genetic testing","authors":"Gráinne Butler, David J. Amor, Catherine Quinlan","doi":"10.1038/s41431-025-01953-3","DOIUrl":"10.1038/s41431-025-01953-3","url":null,"abstract":"Reproductive genetic carrier screening (RGCS) is expanding in both public and private healthcare. The primary aim is to identify carrier status for genetic disorders, inform reproductive decision making and promote reproductive autonomy. As screening panels have increased, the potential for findings with personal health implications rises. We report the prevalence of COL4A3/COL4A4 heterozygous variants within a population undergoing RGCS in a private setting and propose a comprehensive management plan for the ongoing care of this patient cohort. Acknowledging that comprehensive guidelines exist for genetic testing and management of Alport syndrome as a broad patient group, this communication seeks to highlight the increasingly common finding of autosomal dominant Alport syndrome and proposes accessible and practical strategies for the clinicians encountering these patients.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"293-295"},"PeriodicalIF":4.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181918","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 : 2025-09-26DOI: 10.1038/s41431-025-01949-z
Laura Wedd, Yvonne Hort, Chirag Patel, John A. Sayer, Rocio Rius, Andrew J. Mallett, Denny L. Cottle, Ian M. Smyth, Timothy Furlong, John Shine, Amali Mallawaarachchi
Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5′untranslated region (UTR). We then designed a PKD1 5′UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.−69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5′UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5′UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5′-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5′UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.
{"title":"PKD1 5’UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development","authors":"Laura Wedd, Yvonne Hort, Chirag Patel, John A. Sayer, Rocio Rius, Andrew J. Mallett, Denny L. Cottle, Ian M. Smyth, Timothy Furlong, John Shine, Amali Mallawaarachchi","doi":"10.1038/s41431-025-01949-z","DOIUrl":"10.1038/s41431-025-01949-z","url":null,"abstract":"Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5′untranslated region (UTR). We then designed a PKD1 5′UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.−69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5′UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5′UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5′-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5′UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"61-69"},"PeriodicalIF":4.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01949-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174183","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 : 2025-09-25DOI: 10.1038/s41431-025-01938-2
Liedewei Van de Vondel, Jonathan De Winter, Alice Monticelli, Natacha Camacho, Tine Deconinck, Katrien Janssens, Goedele Malfroid, Alicia Alonso-Jiménez, German Demidov, Steven Laurie, Willem De Ridder, Biljana Ermanoska, Vincent Timmerman, Jonathan Baets
We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The deletion was detected through exome-sequencing based copy number variant (CNV) detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin. SPTAN1 loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role of SPTAN1 haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.
我们报告了一个患有儿童期远端肌无力的家族，其中包含SPTAN1基因的杂合染色体9q34缺失。该缺失是通过基于外显子组测序的拷贝数变异（CNV）检测检测到的，在4名患者中分离，在另外2名亲属中非渗透。肌电图，肌肉MRI和肌肉活检显示肌病表型。使用qPCR和western blotting对患者来源的成纤维细胞研究了缺失的细胞后果，结果显示RNA减少，但蛋白质水平没有减少。肌肉组织免疫细胞化学未发现α- ii -谱素减少。SPTAN1功能丧失变异曾被报道引起远端遗传性运动神经病变和最近的远端肌病。在这里，我们证实SPTAN1单倍体功能不全是远端肌病的一个原因。我们提出了α- ii -谱蛋白的年龄依赖性缺乏，并建议在重定向外显子组测序中检测CNV作为重要的诊断工具。
{"title":"A heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy","authors":"Liedewei Van de Vondel, Jonathan De Winter, Alice Monticelli, Natacha Camacho, Tine Deconinck, Katrien Janssens, Goedele Malfroid, Alicia Alonso-Jiménez, German Demidov, Steven Laurie, Willem De Ridder, Biljana Ermanoska, Vincent Timmerman, Jonathan Baets","doi":"10.1038/s41431-025-01938-2","DOIUrl":"10.1038/s41431-025-01938-2","url":null,"abstract":"We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The deletion was detected through exome-sequencing based copy number variant (CNV) detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin. SPTAN1 loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role of SPTAN1 haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"45-52"},"PeriodicalIF":4.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01938-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148261","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 : 2025-09-24DOI: 10.1038/s41431-025-01950-6
Safa Omran, Siew Hua Gan, Siew Li Teoh
Pharmacogenomics is rapidly transforming precision medicine, yet regulatory policies governing its implementation vary widely across countries. This review aims to provide a global perspective on pharmacogenomics guidelines, with a particular focus on high-risk drug reactions such as carbamazepine therapy-induced severe cutaneous adverse reactions. Carbamazepine was selected as a representative example due to its inclusion on the World Health Organization’s essential medicines list and its well-documented association with high-risk alleles, which are linked to severe cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis—conditions with significant mortality rates. Two databases, Overton and Dimensions, were searched to identify relevant national guidelines and policy documents in English. Countries were identified based on document availability and access to governmental sources. The review revealed that all examined countries recognized genetic variation in carbamazepine response within their guidelines, showing notable consistency. However, religious implications related to pharmacogenomics were largely absent. The findings also indicated a growing global momentum toward integrating pharmacogenomics into healthcare systems, although the depth and scope of regulation differ. The United States stands out for its comprehensive pharmacogenomics policy framework, which extends to clinical and industry settings. Lessons from the U.S. model can inform policy development in other regions, tailored to each country’s healthcare infrastructure and cultural context. In conclusion, global harmonization of pharmacogenomics policies is essential to foster international collaboration, enable data sharing, and enhance the safe and equitable implementation of pharmacogenomics in clinical practice.
{"title":"Pharmacogenomics in drug therapy: global regulatory guidelines for managing high-risk drug reactions","authors":"Safa Omran, Siew Hua Gan, Siew Li Teoh","doi":"10.1038/s41431-025-01950-6","DOIUrl":"10.1038/s41431-025-01950-6","url":null,"abstract":"Pharmacogenomics is rapidly transforming precision medicine, yet regulatory policies governing its implementation vary widely across countries. This review aims to provide a global perspective on pharmacogenomics guidelines, with a particular focus on high-risk drug reactions such as carbamazepine therapy-induced severe cutaneous adverse reactions. Carbamazepine was selected as a representative example due to its inclusion on the World Health Organization’s essential medicines list and its well-documented association with high-risk alleles, which are linked to severe cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis—conditions with significant mortality rates. Two databases, Overton and Dimensions, were searched to identify relevant national guidelines and policy documents in English. Countries were identified based on document availability and access to governmental sources. The review revealed that all examined countries recognized genetic variation in carbamazepine response within their guidelines, showing notable consistency. However, religious implications related to pharmacogenomics were largely absent. The findings also indicated a growing global momentum toward integrating pharmacogenomics into healthcare systems, although the depth and scope of regulation differ. The United States stands out for its comprehensive pharmacogenomics policy framework, which extends to clinical and industry settings. Lessons from the U.S. model can inform policy development in other regions, tailored to each country’s healthcare infrastructure and cultural context. In conclusion, global harmonization of pharmacogenomics policies is essential to foster international collaboration, enable data sharing, and enhance the safe and equitable implementation of pharmacogenomics in clinical practice.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"27-36"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01950-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136870","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 : 2025-09-23DOI: 10.1038/s41431-025-01942-6
Enrico Attardi, Marcin W Wlodarski
{"title":"LNKing genotype to phenotype: the expanding clinical spectrum of SH2B3 disorders.","authors":"Enrico Attardi, Marcin W Wlodarski","doi":"10.1038/s41431-025-01942-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01942-6","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130378","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 : 2025-09-23DOI: 10.1038/s41431-025-01943-5
Melek Trigui, Nathalie Pallares-Ruiz, David Geneviève, Cyril Amouroux, Thomas Edouard, Sabine Sigaudy, Marjolaine Willems, Mouna Barat-Houari
Short stature is a prevalent clinical manifestation in children. While certain causes of short stature can be readily identifiable through routine biological tests, often physicians struggle to ascertain any underlying pathogenic cause, resulting in the diagnosis of idiopathic short stature (ISS). Aggrecan, encoded by ACAN, plays a crucial role in cartilage function and bone growth. The aim of our study is to establish a genotype-phenotype correlation in 24 patients carrying distinct ACAN variants. We conducted a panel-based analysis, including 82 genes associated with genetic skeletal disorders and/or short stature, in 388 French patients who consulted for short stature and/or or skeletal features. Genotype-phenotype correlation analysis was performed for all included subjects. Of all positive patients, 24 (≃20%) were found to carry pathogenic or likely pathogenic ACAN variants distributed across the gene, 20 of which had not been previously reported. We report 23 heterozygous cases and one original case with a homozygous SNV. Two patients harboured the same novel nonsense variant, yet exhibited different phenotypes. Familial studies performed in 21 families demonstrated that ACAN variants were inherited in 20 cases. The cohort demonstrated marked phenotypic heterogeneity, even among affected members within the same family. Radiological skeletal abnormalities were observed in 66% of patients. A comprehensive genomic approach is crucial to identify the true proportion of ISS with a monogenic condition. Our results expand the number of pathogenic ACAN variants with their associated phenotypic spectrum. Aggrecanopathies are heterogeneous and particularly frequent in apparently ISS, even without overt skeletal dysplasia.
{"title":"Expanding the molecular spectrum of aggrecanopathies: exploring 24 patients with ACAN significant variants","authors":"Melek Trigui, Nathalie Pallares-Ruiz, David Geneviève, Cyril Amouroux, Thomas Edouard, Sabine Sigaudy, Marjolaine Willems, Mouna Barat-Houari","doi":"10.1038/s41431-025-01943-5","DOIUrl":"10.1038/s41431-025-01943-5","url":null,"abstract":"Short stature is a prevalent clinical manifestation in children. While certain causes of short stature can be readily identifiable through routine biological tests, often physicians struggle to ascertain any underlying pathogenic cause, resulting in the diagnosis of idiopathic short stature (ISS). Aggrecan, encoded by ACAN, plays a crucial role in cartilage function and bone growth. The aim of our study is to establish a genotype-phenotype correlation in 24 patients carrying distinct ACAN variants. We conducted a panel-based analysis, including 82 genes associated with genetic skeletal disorders and/or short stature, in 388 French patients who consulted for short stature and/or or skeletal features. Genotype-phenotype correlation analysis was performed for all included subjects. Of all positive patients, 24 (≃20%) were found to carry pathogenic or likely pathogenic ACAN variants distributed across the gene, 20 of which had not been previously reported. We report 23 heterozygous cases and one original case with a homozygous SNV. Two patients harboured the same novel nonsense variant, yet exhibited different phenotypes. Familial studies performed in 21 families demonstrated that ACAN variants were inherited in 20 cases. The cohort demonstrated marked phenotypic heterogeneity, even among affected members within the same family. Radiological skeletal abnormalities were observed in 66% of patients. A comprehensive genomic approach is crucial to identify the true proportion of ISS with a monogenic condition. Our results expand the number of pathogenic ACAN variants with their associated phenotypic spectrum. Aggrecanopathies are heterogeneous and particularly frequent in apparently ISS, even without overt skeletal dysplasia.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1647-1654"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130461","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 : 2025-09-22DOI: 10.1038/s41431-025-01941-7
Tamara Gjorgjieva, Noah A Rosenberg
Genetic record-matching is a technique by which profiles with one set of genetic markers can be queried against databases of profiles with a different set of markers to determine if profiles containing different marker sets trace to the same individual. In forensic genetics, the potential for using genetic record-matching to test single-nucleotide polymorphism (SNP) profiles for genetic matches to short-tandem repeat (STR) profiles could enable development of backward-compatible SNP marker systems to ultimately replace existing forensic STR systems. This study aims to identify minimal SNP sets for achieving record-matching accuracies comparable to those previously observed with tens or hundreds of thousands of SNPs. Using phased SNP-STR reference data in a worldwide panel of individuals, we evaluate record-matching accuracy with SNP sets chosen by each of a variety of SNP selection strategies. When selecting SNPs randomly, ~9000 SNPs are required for achieving record-matching accuracy comparable to that seen with the full SNP set in the "needle-in-haystack" matching scenario, namely 99% of SNP and STR profiles correctly paired with no false-positive identifications in the median accuracy for test sets of size 626 profile pairs. Selecting SNPs based on various thresholds for their minimal minor allele frequency and physical distance to the STR, however, panels of 1800 SNPs, and as few as 900 SNPs, suffice. These results advance toward a potential minimal size for backward-compatible forensic SNP systems that proceed by genetic record-matching.
{"title":"Toward minimal SNP sets for record-matching with CODIS STR profiles.","authors":"Tamara Gjorgjieva, Noah A Rosenberg","doi":"10.1038/s41431-025-01941-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01941-7","url":null,"abstract":"<p><p>Genetic record-matching is a technique by which profiles with one set of genetic markers can be queried against databases of profiles with a different set of markers to determine if profiles containing different marker sets trace to the same individual. In forensic genetics, the potential for using genetic record-matching to test single-nucleotide polymorphism (SNP) profiles for genetic matches to short-tandem repeat (STR) profiles could enable development of backward-compatible SNP marker systems to ultimately replace existing forensic STR systems. This study aims to identify minimal SNP sets for achieving record-matching accuracies comparable to those previously observed with tens or hundreds of thousands of SNPs. Using phased SNP-STR reference data in a worldwide panel of individuals, we evaluate record-matching accuracy with SNP sets chosen by each of a variety of SNP selection strategies. When selecting SNPs randomly, ~9000 SNPs are required for achieving record-matching accuracy comparable to that seen with the full SNP set in the \"needle-in-haystack\" matching scenario, namely 99% of SNP and STR profiles correctly paired with no false-positive identifications in the median accuracy for test sets of size 626 profile pairs. Selecting SNPs based on various thresholds for their minimal minor allele frequency and physical distance to the STR, however, panels of 1800 SNPs, and as few as 900 SNPs, suffice. These results advance toward a potential minimal size for backward-compatible forensic SNP systems that proceed by genetic record-matching.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124224","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 : 2025-09-22DOI: 10.1038/s41431-025-01937-3
Marlène Malbos, Thierry Gautier, Amelle Shillington, Estelle Colin, Xavier Le Guillou, Oana Caluseriu, Bertrand Isidor, Benjamin Cogné, Cyril Mignot, Boris Keren, Sacha Weber, Clémence Jacquin, Tracy Dudding, Daniel Calame, Juliette Piard, Jonathan Levy, Xenia Latypova, Alain Verloes, Tanguy Niclass, Aurélia Jacquette, Lori White, Marie-Pierre Moizard, Hélène Dollfus, Sébastien Moutton, Julian Delanne, Caroline Racine, Quentin Thomas, Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Ange-Line Bruel, Hana Safraou, Christophe Philippe, Yannis Duffourd, Christel Thauvin-Robinet, Jérôme Govin, Antonio Vitobello, Laurence Faivre
SAP102, a member of the membrane-associated guanylate kinase proteins family, is a scaffolding protein encoded by the DLG3 gene whose hemizygous variants with loss-of-function effect are associated with X-linked Intellectual developmental disorder 90. We gathered international data from 17 new individuals with 16 different DLG3 variants (10 with pathogenic loss-of-function and 6 variants of uncertain significance), and reviewed genotypic and phenotypic data from 37 previously published families with 34 different variants. Using family segregation, frequency in publication databases, protein structure modelling and in silico prediction scores, we reclassified six missense variants (five from the literature and one common to our cohort and the literature) as likely benign. Among the individuals newly reported with likely pathogenic or pathogenic DLG3 variants, intellectual disability was more frequently associated with morphological features than in the literature, leading to a proposed extension of the associated X-linked intellectual developmental disorder 90 to a more syndromic neurodevelopmental disorder. In conclusion, we provide here an international clinical series of novel individuals with DLG3 variants in order to better define the clinical and molecular spectrum associated with this condition, and a review of the literature.
{"title":"Further phenotypical delineation of DLG3-related neurodevelopmental disorders","authors":"Marlène Malbos, Thierry Gautier, Amelle Shillington, Estelle Colin, Xavier Le Guillou, Oana Caluseriu, Bertrand Isidor, Benjamin Cogné, Cyril Mignot, Boris Keren, Sacha Weber, Clémence Jacquin, Tracy Dudding, Daniel Calame, Juliette Piard, Jonathan Levy, Xenia Latypova, Alain Verloes, Tanguy Niclass, Aurélia Jacquette, Lori White, Marie-Pierre Moizard, Hélène Dollfus, Sébastien Moutton, Julian Delanne, Caroline Racine, Quentin Thomas, Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Ange-Line Bruel, Hana Safraou, Christophe Philippe, Yannis Duffourd, Christel Thauvin-Robinet, Jérôme Govin, Antonio Vitobello, Laurence Faivre","doi":"10.1038/s41431-025-01937-3","DOIUrl":"10.1038/s41431-025-01937-3","url":null,"abstract":"SAP102, a member of the membrane-associated guanylate kinase proteins family, is a scaffolding protein encoded by the DLG3 gene whose hemizygous variants with loss-of-function effect are associated with X-linked Intellectual developmental disorder 90. We gathered international data from 17 new individuals with 16 different DLG3 variants (10 with pathogenic loss-of-function and 6 variants of uncertain significance), and reviewed genotypic and phenotypic data from 37 previously published families with 34 different variants. Using family segregation, frequency in publication databases, protein structure modelling and in silico prediction scores, we reclassified six missense variants (five from the literature and one common to our cohort and the literature) as likely benign. Among the individuals newly reported with likely pathogenic or pathogenic DLG3 variants, intellectual disability was more frequently associated with morphological features than in the literature, leading to a proposed extension of the associated X-linked intellectual developmental disorder 90 to a more syndromic neurodevelopmental disorder. In conclusion, we provide here an international clinical series of novel individuals with DLG3 variants in order to better define the clinical and molecular spectrum associated with this condition, and a review of the literature.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 12","pages":"1585-1595"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124195","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}
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