Pub Date : 2025-07-31DOI: 10.1038/s41431-025-01918-6
Leo Arkush, Geeske M. van Woerden, Limor Ziv, Dina Marek-Yagel, Reginald Fonseca, Esmee Brevé, Ortal Barel, Nechama Shalva, Alvit Veber, Yair Anikster, Dominique Ben-Ami Raichman, Banan Musallam, Shai Marcu, Andreea Nissenkorn, Hanna Mandel, Steven A. Kushner, Bruria Ben Zeev, Gali Heimer
Pontocerebellar hypoplasia (PCH) represents a group of disorders characterized by cerebellum and pons hypoplasia, variable cerebral involvement, microcephaly, severe global developmental delay (GDD), and seizures. We sought the genetic cause of PCH in two siblings. Genetic workup was performed by whole-exome sequencing followed by Sanger validation. Morpholino-knockdown zebrafish embryos with human wild-type gene rescue were used to assess cerebellar development and motor function. Transfected mouse hippocampal cultures and electroporated mouse embryos were employed to assess functional effects on neuronal morphology and development. Both patients presented with profound GDD, severe microcephaly, cataracts, and variably seizures. Their MRIs demonstrated marked cerebellar and pontine hypoplasia. Both were homozygous for a c.416T > C, p.(Leu139Pro) MED29 variant which was predicted to be pathogenic. Locomotion and cerebellar GABAergic neurons development were both impaired in MED29 Morpholino-knockdown zebrafish and rescued by human wild-type gene expression. ShRNA-knockdown of MED29 in mouse hippocampal neurons decreased neurite length and arborization in vitro, and caused defective embryonic neuronal migration in vivo. Overexpression of MED29 p.(Leu139Pro) was consistent with a loss-of-function. Taken together, the Mediator complex regulates transcription processes, and defects in particular subunits are associated with distinct neurodevelopmental phenotypes involving PCH. We conclude that MED29 is a novel risk gene for PCH.
{"title":"Biallelic MED29 variants cause pontocerebellar hypoplasia with cataracts","authors":"Leo Arkush, Geeske M. van Woerden, Limor Ziv, Dina Marek-Yagel, Reginald Fonseca, Esmee Brevé, Ortal Barel, Nechama Shalva, Alvit Veber, Yair Anikster, Dominique Ben-Ami Raichman, Banan Musallam, Shai Marcu, Andreea Nissenkorn, Hanna Mandel, Steven A. Kushner, Bruria Ben Zeev, Gali Heimer","doi":"10.1038/s41431-025-01918-6","DOIUrl":"10.1038/s41431-025-01918-6","url":null,"abstract":"Pontocerebellar hypoplasia (PCH) represents a group of disorders characterized by cerebellum and pons hypoplasia, variable cerebral involvement, microcephaly, severe global developmental delay (GDD), and seizures. We sought the genetic cause of PCH in two siblings. Genetic workup was performed by whole-exome sequencing followed by Sanger validation. Morpholino-knockdown zebrafish embryos with human wild-type gene rescue were used to assess cerebellar development and motor function. Transfected mouse hippocampal cultures and electroporated mouse embryos were employed to assess functional effects on neuronal morphology and development. Both patients presented with profound GDD, severe microcephaly, cataracts, and variably seizures. Their MRIs demonstrated marked cerebellar and pontine hypoplasia. Both were homozygous for a c.416T > C, p.(Leu139Pro) MED29 variant which was predicted to be pathogenic. Locomotion and cerebellar GABAergic neurons development were both impaired in MED29 Morpholino-knockdown zebrafish and rescued by human wild-type gene expression. ShRNA-knockdown of MED29 in mouse hippocampal neurons decreased neurite length and arborization in vitro, and caused defective embryonic neuronal migration in vivo. Overexpression of MED29 p.(Leu139Pro) was consistent with a loss-of-function. Taken together, the Mediator complex regulates transcription processes, and defects in particular subunits are associated with distinct neurodevelopmental phenotypes involving PCH. We conclude that MED29 is a novel risk gene for PCH.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1271-1280"},"PeriodicalIF":4.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01918-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759561","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 : 2025-07-31DOI: 10.1038/s41431-025-01922-w
Hans Ehrencrona, Anna Öfverholm, Carolina Hawranek, Lovisa Lovmar, Sara Svensson, Sigrid Wennstedt, Barbro Hellquist, Anna Rosén
Observational studies suggest that direct contact from healthcare to at-risk relatives may increase genetic counselling (GC) uptake as compared to family-mediated risk disclosure, but randomised controlled trials (RCTs) are lacking. This study assessed whether the offer of direct letters to relatives at risk of hereditary breast and ovarian cancer (HBOC) or Lynch syndrome increases GC uptake compared to family-mediated communication alone. Between 2020 and 2023, probands were randomly assigned to family-mediated disclosure (control) or family-mediated disclosure plus the offer of sending direct letters to at-risk relatives (intervention). The primary outcome was GC uptake within 12 months, measured as the proportion of eligible relatives at risk contacting a Swedish cancer genetics clinic. In total, 165 families (median: 4 eligible relatives, range: 1–26) were randomised to control (n = 79) or intervention (n = 86). GC uptake was 67% in controls and 71% in the intervention group (P = 0.23). After adjusting for predefined variables and covariates, there was still no significant difference between groups (OR: 1.24, CI: 0.79–1.95, P = 0.34). Distant relatives had lower uptake than first-degree relatives (OR: 0.27, CI: 0.18–0.40, P < 0.001), while female relatives had higher uptake than males (OR: 2.17, CI: 1.50–3.12, P < 0.001). This is the largest RCT so far investigating direct letters to relatives. GC uptake was high in both groups, and the intervention of direct letters did not show superiority over family-mediated communication alone. Direct letters to relatives may complement family-mediated disclosure in certain situations, but should not be implemented as a general procedure in cancer genetics practices.
观察性研究表明，与家庭介导的风险披露相比，医疗机构与高危亲属的直接接触可能会增加遗传咨询（GC）的吸收，但缺乏随机对照试验（RCTs）。本研究评估了与单独的家庭沟通相比，向有遗传性乳腺癌和卵巢癌（HBOC）或Lynch综合征风险的亲属提供直接信函是否会增加GC摄取。在2020年至2023年期间，先证者被随机分配到家庭介导的披露组（对照组）或家庭介导的披露组，并提供直接向有风险的亲属发送信件（干预组）。主要结果是12个月内的GC摄取，以符合条件的高危亲属联系瑞典癌症遗传学诊所的比例来衡量。共有165个家庭（中位数：4个符合条件的亲属，范围：1-26）被随机分为对照组（n = 79）或干预组（n = 86）。对照组GC摄取率67%，干预组71% （P = 0.23）。在调整预定义变量和协变量后，组间仍无显著差异（OR: 1.24, CI: 0.79-1.95, P = 0.34）。远亲摄取量低于一级亲缘(OR: 0.27, CI: 0.18-0.40， P
{"title":"Direct letters to relatives at risk of hereditary cancer—a randomised trial on healthcare-assisted versus family-mediated risk disclosure","authors":"Hans Ehrencrona, Anna Öfverholm, Carolina Hawranek, Lovisa Lovmar, Sara Svensson, Sigrid Wennstedt, Barbro Hellquist, Anna Rosén","doi":"10.1038/s41431-025-01922-w","DOIUrl":"10.1038/s41431-025-01922-w","url":null,"abstract":"Observational studies suggest that direct contact from healthcare to at-risk relatives may increase genetic counselling (GC) uptake as compared to family-mediated risk disclosure, but randomised controlled trials (RCTs) are lacking. This study assessed whether the offer of direct letters to relatives at risk of hereditary breast and ovarian cancer (HBOC) or Lynch syndrome increases GC uptake compared to family-mediated communication alone. Between 2020 and 2023, probands were randomly assigned to family-mediated disclosure (control) or family-mediated disclosure plus the offer of sending direct letters to at-risk relatives (intervention). The primary outcome was GC uptake within 12 months, measured as the proportion of eligible relatives at risk contacting a Swedish cancer genetics clinic. In total, 165 families (median: 4 eligible relatives, range: 1–26) were randomised to control (n = 79) or intervention (n = 86). GC uptake was 67% in controls and 71% in the intervention group (P = 0.23). After adjusting for predefined variables and covariates, there was still no significant difference between groups (OR: 1.24, CI: 0.79–1.95, P = 0.34). Distant relatives had lower uptake than first-degree relatives (OR: 0.27, CI: 0.18–0.40, P < 0.001), while female relatives had higher uptake than males (OR: 2.17, CI: 1.50–3.12, P < 0.001). This is the largest RCT so far investigating direct letters to relatives. GC uptake was high in both groups, and the intervention of direct letters did not show superiority over family-mediated communication alone. Direct letters to relatives may complement family-mediated disclosure in certain situations, but should not be implemented as a general procedure in cancer genetics practices.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1359-1367"},"PeriodicalIF":4.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01922-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759562","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 : 2025-07-29DOI: 10.1038/s41431-025-01917-7
Amy Clark, Emily DeBortoli, Marisa Blancoe, Christopher Sgro, Tenielle Clinch, Mariana Melo, Alberto Pinzon-Charry, Anna Sullivan, Aideen McInerney-Leo, Jane Peake, Peter McNaughton, Tatiane Yanes
Genomic testing has become essential to diagnosing and managing paediatric inborn errors of immunity (IEI), necessitating the development of mainstream models of care to facilitate optimal delivery of testing. However, little is known about the experiences of families undergoing paediatric IEI genomic testing within mainstream settings and parental experiences with such conditions remain underexplored. Thus, this study aimed to describe the experiences of parents of children who underwent mainstreamed IEI genomic testing. Semi-structured interviews were conducted with 17 parents (14 mothers and 3 fathers) of children with an IEI and thematically analysed. Six themes captured (i) the diverse dimensions of distress related to paediatric IEI, (ii) the associated social, practical and financial implications, (iii) the involvement of children in their care, (iv) parental satisfaction with mainstreamed genomic testing, (v) the value of multidisciplinary care, and (vi) considerations surrounding genomic testing decision-making. Findings highlight the significant psychosocial impacts of paediatric IEI, including distinct social and emotional challenges. High satisfaction with mainstreamed IEI genomic testing was reported by all parents. Recommendations for improvement include developing tailored resources to address families ongoing psychoeducational needs, enhancing mental health support, and involving children appropriately. Collectively, these findings substantiate the benefits of mainstreamed IEI genomic testing, while expanding literature on the psychosocial impact of such paediatric conditions. Further exploration of families and children’s needs and development of tailored resources are essential to ensure the delivery of patient-centred care.
{"title":"“It’s a Godsend”: Parental experiences of genomic testing for paediatric inborn errors of immunity","authors":"Amy Clark, Emily DeBortoli, Marisa Blancoe, Christopher Sgro, Tenielle Clinch, Mariana Melo, Alberto Pinzon-Charry, Anna Sullivan, Aideen McInerney-Leo, Jane Peake, Peter McNaughton, Tatiane Yanes","doi":"10.1038/s41431-025-01917-7","DOIUrl":"10.1038/s41431-025-01917-7","url":null,"abstract":"Genomic testing has become essential to diagnosing and managing paediatric inborn errors of immunity (IEI), necessitating the development of mainstream models of care to facilitate optimal delivery of testing. However, little is known about the experiences of families undergoing paediatric IEI genomic testing within mainstream settings and parental experiences with such conditions remain underexplored. Thus, this study aimed to describe the experiences of parents of children who underwent mainstreamed IEI genomic testing. Semi-structured interviews were conducted with 17 parents (14 mothers and 3 fathers) of children with an IEI and thematically analysed. Six themes captured (i) the diverse dimensions of distress related to paediatric IEI, (ii) the associated social, practical and financial implications, (iii) the involvement of children in their care, (iv) parental satisfaction with mainstreamed genomic testing, (v) the value of multidisciplinary care, and (vi) considerations surrounding genomic testing decision-making. Findings highlight the significant psychosocial impacts of paediatric IEI, including distinct social and emotional challenges. High satisfaction with mainstreamed IEI genomic testing was reported by all parents. Recommendations for improvement include developing tailored resources to address families ongoing psychoeducational needs, enhancing mental health support, and involving children appropriately. Collectively, these findings substantiate the benefits of mainstreamed IEI genomic testing, while expanding literature on the psychosocial impact of such paediatric conditions. Further exploration of families and children’s needs and development of tailored resources are essential to ensure the delivery of patient-centred care.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1342-1349"},"PeriodicalIF":4.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01917-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741724","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 : 2025-07-29DOI: 10.1038/s41431-025-01915-9
Tooba Aleem, Maliha Rashid, Naeem Ahmad, Muhammad Farrukh Asif, Muhammad Tariq, Naveed Altaf Malik, James A. Poulter
Neuromuscular disorders comprise the majority of neurogenetic conditions, generally characterized by overlapping clinical symptoms, such as spastic paraplegia, muscular abnormalities, and ataxia. In low- and middle-income countries (LMICs), many patients remain undiagnosed or are misdiagnosed. For many NMDs, early diagnosis helps reduce the impact and mortality of the disorder, particularly in LMICs such as Pakistan, and reduces the burden on the healthcare system. The aim of this study was to use exome sequencing as a first line of diagnostic approach to identify the cause of disease. Here, we present five consanguineous families from different remote villages in Pakistan with an undiagnosed neuromuscular disorder, in whom whole-exome sequencing was able to provide a diagnosis. We identified novel variants in known reported disease genes SPEN (c.351_356del) and POMT1 (c.1583A > G) and three previously reported variants in MMP2 (c.1287del), ARL13B (c.599 G > A), and SPG11 (c.6811_6812del). In one family, homozygous pathogenic variants in two different genes (SPEN and NPHP4) were identified; to our knowledge, this is the first report of nephronophthisis and Radio-Tartaglia syndrome co- segregating in a family. In all cases, Sanger sequencing was performed on available family members to confirm segregation. Our study highlights the importance of whole-exome sequencing as a first-line diagnostic approach in undiagnosed individuals with neuromuscular disorders in LMICs, where access to healthcare is limited.
{"title":"Exome sequencing reveals broad genetic heterogeneity for neuromuscular disorders in consanguineous Pakistani Families","authors":"Tooba Aleem, Maliha Rashid, Naeem Ahmad, Muhammad Farrukh Asif, Muhammad Tariq, Naveed Altaf Malik, James A. Poulter","doi":"10.1038/s41431-025-01915-9","DOIUrl":"10.1038/s41431-025-01915-9","url":null,"abstract":"Neuromuscular disorders comprise the majority of neurogenetic conditions, generally characterized by overlapping clinical symptoms, such as spastic paraplegia, muscular abnormalities, and ataxia. In low- and middle-income countries (LMICs), many patients remain undiagnosed or are misdiagnosed. For many NMDs, early diagnosis helps reduce the impact and mortality of the disorder, particularly in LMICs such as Pakistan, and reduces the burden on the healthcare system. The aim of this study was to use exome sequencing as a first line of diagnostic approach to identify the cause of disease. Here, we present five consanguineous families from different remote villages in Pakistan with an undiagnosed neuromuscular disorder, in whom whole-exome sequencing was able to provide a diagnosis. We identified novel variants in known reported disease genes SPEN (c.351_356del) and POMT1 (c.1583A > G) and three previously reported variants in MMP2 (c.1287del), ARL13B (c.599 G > A), and SPG11 (c.6811_6812del). In one family, homozygous pathogenic variants in two different genes (SPEN and NPHP4) were identified; to our knowledge, this is the first report of nephronophthisis and Radio-Tartaglia syndrome co- segregating in a family. In all cases, Sanger sequencing was performed on available family members to confirm segregation. Our study highlights the importance of whole-exome sequencing as a first-line diagnostic approach in undiagnosed individuals with neuromuscular disorders in LMICs, where access to healthcare is limited.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1264-1270"},"PeriodicalIF":4.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01915-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741726","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 : 2025-07-29DOI: 10.1038/s41431-025-01919-5
Daphne J. Smits, Christophe Debuy, Alice S. Brooks, Rachel Schot, Federico Ferraro, Dmitrijs Rots, Arjan Bouman, Virginie J. M. Verhoeven, Laura Donker Kaat, Sarina G. Kant, Yolande van Bever, Serwet Demirdas, Shimriet Zeidler, Marieke F. van Dooren, Stephany H. Donze, Lies H. Hoefsloot, Marjon A. van Slegtenhorst, Martina Wilke, Frank Sleutels, Mark Drost, Hennie T. Brüggenwirth, Rick van Minkelen, Anne Goverde, Janna A. Hol, Ingrid M. B. H. van de Laar, Yvette van Ierland, Anneke Kievit, Vyne van der Schoot, Kyra E. Stuurman, Grazia M. S. Mancini, Marja W. Wessels, Tjakko J. van Ham, Tjitske Kleefstra, Tahsin Stefan Barakat
Disease-causing variants in chromatin regulator genes cause many developmental disorders. DNA methylation (DNAm) signatures are emerging as a diagnostic tool to identify disease causes and classify variants of uncertain significance (VUS). This study evaluates their diagnostic utility in a routine clinical setting. We retrospectively analyzed 298 patients from the Erasmus MC who underwent DNAm signature testing using the commercial EpisignTM platform between February 2019 and June 2023. The cohort included 75 targeted analyses for follow-up on prior genetic findings and 223 complete analyses for cases unsolved after prior diagnostic testing. In the 75 targeted analyses, DNAm signatures were positive in 18% (10/55) for (VUS), 91% (10/11) for likely pathogenic variants, and 89% (8/9) for pathogenic variants. In 223 complete analyses, a disease-linked DNAm signature was observed in 9.0% (20/223), with a (partial) phenotypic match in 55% of those (11/20) but no match in 45% (9/20). In 81.8% (9/11) of those DNAm signature positive cases with a phenotypic match, retrospective analysis identified a causative DNA variant or confirmed independently an imprinting disorder that was unidentified previously, providing valuable diagnostic insights with an overall diagnostic yield of 4.0% (9/223) for these molecular confirmed cases. In conclusion, this study supports the clinical utility of DNAm signatures to assist in interpreting and classifying VUS, but also as a complementary tool when prior genetic testing, including exome sequencing, failed to provide a diagnosis.
{"title":"Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders","authors":"Daphne J. Smits, Christophe Debuy, Alice S. Brooks, Rachel Schot, Federico Ferraro, Dmitrijs Rots, Arjan Bouman, Virginie J. M. Verhoeven, Laura Donker Kaat, Sarina G. Kant, Yolande van Bever, Serwet Demirdas, Shimriet Zeidler, Marieke F. van Dooren, Stephany H. Donze, Lies H. Hoefsloot, Marjon A. van Slegtenhorst, Martina Wilke, Frank Sleutels, Mark Drost, Hennie T. Brüggenwirth, Rick van Minkelen, Anne Goverde, Janna A. Hol, Ingrid M. B. H. van de Laar, Yvette van Ierland, Anneke Kievit, Vyne van der Schoot, Kyra E. Stuurman, Grazia M. S. Mancini, Marja W. Wessels, Tjakko J. van Ham, Tjitske Kleefstra, Tahsin Stefan Barakat","doi":"10.1038/s41431-025-01919-5","DOIUrl":"10.1038/s41431-025-01919-5","url":null,"abstract":"Disease-causing variants in chromatin regulator genes cause many developmental disorders. DNA methylation (DNAm) signatures are emerging as a diagnostic tool to identify disease causes and classify variants of uncertain significance (VUS). This study evaluates their diagnostic utility in a routine clinical setting. We retrospectively analyzed 298 patients from the Erasmus MC who underwent DNAm signature testing using the commercial EpisignTM platform between February 2019 and June 2023. The cohort included 75 targeted analyses for follow-up on prior genetic findings and 223 complete analyses for cases unsolved after prior diagnostic testing. In the 75 targeted analyses, DNAm signatures were positive in 18% (10/55) for (VUS), 91% (10/11) for likely pathogenic variants, and 89% (8/9) for pathogenic variants. In 223 complete analyses, a disease-linked DNAm signature was observed in 9.0% (20/223), with a (partial) phenotypic match in 55% of those (11/20) but no match in 45% (9/20). In 81.8% (9/11) of those DNAm signature positive cases with a phenotypic match, retrospective analysis identified a causative DNA variant or confirmed independently an imprinting disorder that was unidentified previously, providing valuable diagnostic insights with an overall diagnostic yield of 4.0% (9/223) for these molecular confirmed cases. In conclusion, this study supports the clinical utility of DNAm signatures to assist in interpreting and classifying VUS, but also as a complementary tool when prior genetic testing, including exome sequencing, failed to provide a diagnosis.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1281-1289"},"PeriodicalIF":4.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01919-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741725","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 : 2025-07-28DOI: 10.1038/s41431-025-01912-y
Benoit Mazel, Emilia Aisha Coleman, Justine Rousseau, Senthilkumar Kailasam, Norbert Fonya Ajeawung, Daniel Alexander Jimenez Cruz, Sophie Ehresmann, Gang Chen, Carl Ernst, Philippe M. Campeau
Chromosomal microdeletions represent a complex class of genetic disorders. Recently, 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C have gained prominence as structural variants associated with neurodevelopmental disorders, but their occurrence mechanisms remain unexplored. We used a comprehensive range of sequencing technologies (mate pair genome sequencing, linked-pair genome sequencing, nanopore sequencing, targeted locus amplification (TLA), long range and nested PCR followed by Sanger sequencing), to map the exact 16p13.3 microdeletion breakpoints in eight previously reported individuals. Microdeletion breakpoints were successfully mapped in all patients using TLA, split read analysis, PCR/Sanger sequencing, or nanopore sequencing. Alu sequences and/or non-B DNA motifs were detected in all patients. Mechanistic analysis identified distinct pathways underlying these rearrangements. Noteworthy, two unrelated individuals carried identical microdeletions that might have been mediated by an atypical form of non-allelic homologous recombination, given the presence of a 639 bp sequence with 96.2% homology. Microhomology-mediated end-joining and non-homologous end-joining emerged as other mechanisms driving these 16p13.3 microdeletions, which differs from other studied contiguous gene deletion syndromes. This research contributes to a deeper understanding of microdeletion-associated disorder pathophysiology in medical genetics.
{"title":"Mechanistic insights into 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C through advanced sequencing approaches","authors":"Benoit Mazel, Emilia Aisha Coleman, Justine Rousseau, Senthilkumar Kailasam, Norbert Fonya Ajeawung, Daniel Alexander Jimenez Cruz, Sophie Ehresmann, Gang Chen, Carl Ernst, Philippe M. Campeau","doi":"10.1038/s41431-025-01912-y","DOIUrl":"10.1038/s41431-025-01912-y","url":null,"abstract":"Chromosomal microdeletions represent a complex class of genetic disorders. Recently, 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C have gained prominence as structural variants associated with neurodevelopmental disorders, but their occurrence mechanisms remain unexplored. We used a comprehensive range of sequencing technologies (mate pair genome sequencing, linked-pair genome sequencing, nanopore sequencing, targeted locus amplification (TLA), long range and nested PCR followed by Sanger sequencing), to map the exact 16p13.3 microdeletion breakpoints in eight previously reported individuals. Microdeletion breakpoints were successfully mapped in all patients using TLA, split read analysis, PCR/Sanger sequencing, or nanopore sequencing. Alu sequences and/or non-B DNA motifs were detected in all patients. Mechanistic analysis identified distinct pathways underlying these rearrangements. Noteworthy, two unrelated individuals carried identical microdeletions that might have been mediated by an atypical form of non-allelic homologous recombination, given the presence of a 639 bp sequence with 96.2% homology. Microhomology-mediated end-joining and non-homologous end-joining emerged as other mechanisms driving these 16p13.3 microdeletions, which differs from other studied contiguous gene deletion syndromes. This research contributes to a deeper understanding of microdeletion-associated disorder pathophysiology in medical genetics.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1136-1143"},"PeriodicalIF":4.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729003","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 : 2025-07-24DOI: 10.1038/s41431-025-01893-y
Martin Bird, Chris Jyun-Peng Tung, Alan M Pittman, Elijah R Behr, Axel Nohturfft, Marta Futema
Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH.
{"title":"Novel start codon variant in the 5'UTR of LDLR associated with familial hypercholesterolaemia.","authors":"Martin Bird, Chris Jyun-Peng Tung, Alan M Pittman, Elijah R Behr, Axel Nohturfft, Marta Futema","doi":"10.1038/s41431-025-01893-y","DOIUrl":"https://doi.org/10.1038/s41431-025-01893-y","url":null,"abstract":"<p><p>Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706870","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 : 2025-07-23DOI: 10.1038/s41431-025-01911-z
Young-gon Kim, Changhee Ha, Ja-Hyun Jang, Mi-Ae Jang, Jong-Won Kim
Recently, new clinical genome resource (ClinGen) guidance focusing on cosegregation (PP1) and phenotype-specificity criteria (PP4) were introduced, based on the observation that the phenotype specificity could provide greater level of pathogenicity evidence. This study aimed to reassess variants of uncertain significance (VUS) found in tumor suppressor genes with specific phenotypes using these new recommendations. We retrieved VUS from an in-house database of all germline variants detected using sequencing since 2008. Patients carrying VUS from seven target tumor suppressor genes, NF1, TSC1, TSC2, RB1, PTCH1, STK11, and FH, were selected and the pathogenicity of each variant was reassessed using the new ClinGen PP1/PP4 criteria. In total, 128 unique VUS from 145 carriers were evaluated. Initial classification using the classic PP1/PP4 criteria from ACMG/AMP and point-based classification resulted in 21 variants being reclassified (2 pathogenic variants, 3 likely pathogenic variants [LPVs], 15 likely benign variants, and 1 benign variant), leaving 101 VUS. Applying the new ClinGen PP1/PP4 criteria, 32 (31.4%) remaining VUS were reclassified as LPVs. The reclassification rate was highest in STK11 (88.9%). Representative cases highlighted successful reclassification owing to highly specific phenotypes aligned with the new criteria. The new ClinGen PP1/PP4 criteria significantly improved the reclassification of VUS in tumor suppressor genes associated with specific phenotypes. The new criteria could substantially enhance the accuracy of variant classification.
{"title":"Reassessment of variants of uncertain significance in tumor suppressor genes using new ClinGen PP1/PP4 criteria guidance","authors":"Young-gon Kim, Changhee Ha, Ja-Hyun Jang, Mi-Ae Jang, Jong-Won Kim","doi":"10.1038/s41431-025-01911-z","DOIUrl":"10.1038/s41431-025-01911-z","url":null,"abstract":"Recently, new clinical genome resource (ClinGen) guidance focusing on cosegregation (PP1) and phenotype-specificity criteria (PP4) were introduced, based on the observation that the phenotype specificity could provide greater level of pathogenicity evidence. This study aimed to reassess variants of uncertain significance (VUS) found in tumor suppressor genes with specific phenotypes using these new recommendations. We retrieved VUS from an in-house database of all germline variants detected using sequencing since 2008. Patients carrying VUS from seven target tumor suppressor genes, NF1, TSC1, TSC2, RB1, PTCH1, STK11, and FH, were selected and the pathogenicity of each variant was reassessed using the new ClinGen PP1/PP4 criteria. In total, 128 unique VUS from 145 carriers were evaluated. Initial classification using the classic PP1/PP4 criteria from ACMG/AMP and point-based classification resulted in 21 variants being reclassified (2 pathogenic variants, 3 likely pathogenic variants [LPVs], 15 likely benign variants, and 1 benign variant), leaving 101 VUS. Applying the new ClinGen PP1/PP4 criteria, 32 (31.4%) remaining VUS were reclassified as LPVs. The reclassification rate was highest in STK11 (88.9%). Representative cases highlighted successful reclassification owing to highly specific phenotypes aligned with the new criteria. The new ClinGen PP1/PP4 criteria significantly improved the reclassification of VUS in tumor suppressor genes associated with specific phenotypes. The new criteria could substantially enhance the accuracy of variant classification.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1368-1375"},"PeriodicalIF":4.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01911-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697924","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 : 2025-07-19DOI: 10.1038/s41431-025-01910-0
Susan M. White, Annelotte P. Wondergem, Isa Breet, Maren Dittmaier, Katrina Bell, Christopher M. Richmond, Winita Hardikar, Kanika Bhatia, Catherine Quinlan, David Orchard, Areetha D’Souza, Walter J. Chazin, Christopher Smith, Rebecca Sparkes, Simon Lam, Alexandra Carter, Robert J. Hopkin, Leticia Khendek, Bonnie R. Sullivan, Naja Becher, Anne Katrine W. Simonsen, Helene Kvistgaard, Katherine Dempsey, Alexander G. Miethke, Pernille Axél Gregersen, Eliza Phillips, Martijn S. Luijsterburg
DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.
{"title":"A new multisystem ERCC1-hepatorenal syndrome: insights from a clinical cohort, molecular pathogenesis, and management guidelines","authors":"Susan M. White, Annelotte P. Wondergem, Isa Breet, Maren Dittmaier, Katrina Bell, Christopher M. Richmond, Winita Hardikar, Kanika Bhatia, Catherine Quinlan, David Orchard, Areetha D’Souza, Walter J. Chazin, Christopher Smith, Rebecca Sparkes, Simon Lam, Alexandra Carter, Robert J. Hopkin, Leticia Khendek, Bonnie R. Sullivan, Naja Becher, Anne Katrine W. Simonsen, Helene Kvistgaard, Katherine Dempsey, Alexander G. Miethke, Pernille Axél Gregersen, Eliza Phillips, Martijn S. Luijsterburg","doi":"10.1038/s41431-025-01910-0","DOIUrl":"10.1038/s41431-025-01910-0","url":null,"abstract":"DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1252-1263"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01910-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667477","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 : 2025-07-18DOI: 10.1038/s41431-025-01908-8
Clara Fabian-Therond
{"title":"Comment on \"Determining a role for Patient and Public Involvement and Engagement (PPIE) in genomic data governance for cancer care.\"","authors":"Clara Fabian-Therond","doi":"10.1038/s41431-025-01908-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01908-8","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667478","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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