Pub Date : 2026-01-01DOI: 10.1016/j.ejmg.2026.105067
Giorgia Buoncuore , Marco Salvatore , Adele Rocchetti , Lorenzo Facciaroni , Edvige Veneselli , Maurizio Elia , Silvia Russo , Michelina Armando , Michele Germano , Tommaso Prisco , Stefano Sartori , Gemma Marinella , Roberta Battini , Giuseppe Gobbi , Paola Torreri , Angelman Syndrome Registry working group
Background
Angelman syndrome (AS) is a rare and heterogeneous genetic disorder characterized by intellectual and psychomotor delay, speech deficits, seizures and behavioural issues. To evaluate the feasibility of collecting data by many Italian centers involved in pathology management, and to investigate the relationship between various symptoms and genotypes, a dedicated AS registry was developed.
This study aims to present preliminary findings from the Italian AS registry (IReAS), with a specific focus on exploring genotype-phenotype correlations.
Materials and methods
The IReAS, established in 2020, aims to collect information from 14 different Italian referral. It includes demography, diagnosis and genetic, patient status, therapeutic interventions and mortality data collection.
Results
213 patients (55.4 % female vs 44.6 % male) were included in the IReAS during the 2020–24 period. Average age at genetic diagnosis was 3.8 years; 63 % of patients was paediatric; 70.4 % of subjects had maternal deletion. Most patients exhibited global developmental delay (100 %), movement disorders (94.8 %), behavioral abnormalities (96.2 %), and a total lack of language development (95.8 %). Epilepsy is also highly prevalent (80.3 %), with a significantly higher incidence in patients with maternal deletion compared to non-deletion groups (88 % vs 61.9 %).
Conclusions
The IReAS provides comprehensive data on the diagnosis, genetic subtypes and clinical features of AS patients. It can facilitate genotype-phenotype correlation analyses, offering insights into the AS natural history and potential implications for research on targeted therapies.
{"title":"The Italian Angelman Syndrome Registry (IReAS): a tool for standardized data collection and genotype-phenotype analysis","authors":"Giorgia Buoncuore , Marco Salvatore , Adele Rocchetti , Lorenzo Facciaroni , Edvige Veneselli , Maurizio Elia , Silvia Russo , Michelina Armando , Michele Germano , Tommaso Prisco , Stefano Sartori , Gemma Marinella , Roberta Battini , Giuseppe Gobbi , Paola Torreri , Angelman Syndrome Registry working group","doi":"10.1016/j.ejmg.2026.105067","DOIUrl":"10.1016/j.ejmg.2026.105067","url":null,"abstract":"<div><h3>Background</h3><div>Angelman syndrome (AS) is a rare and heterogeneous genetic disorder characterized by intellectual and psychomotor delay, speech deficits, seizures and behavioural issues. To evaluate the feasibility of collecting data by many Italian centers involved in pathology management, and to investigate the relationship between various symptoms and genotypes, a dedicated AS registry was developed.</div><div>This study aims to present preliminary findings from the Italian AS registry (IReAS), with a specific focus on exploring genotype-phenotype correlations.</div></div><div><h3>Materials and methods</h3><div>The IReAS, established in 2020, aims to collect information from 14 different Italian referral. It includes demography, diagnosis and genetic, patient status, therapeutic interventions and mortality data collection.</div></div><div><h3>Results</h3><div>213 patients (55.4 % female <em>vs</em> 44.6 % male) were included in the IReAS during the 2020–24 period. Average age at genetic diagnosis was 3.8 years; 63 % of patients was paediatric; 70.4 % of subjects had maternal deletion. Most patients exhibited global developmental delay (100 %), movement disorders (94.8 %), behavioral abnormalities (96.2 %), and a total lack of language development (95.8 %). Epilepsy is also highly prevalent (80.3 %), with a significantly higher incidence in patients with maternal deletion compared to non-deletion groups (88 % <em>vs</em> 61.9 %).</div></div><div><h3>Conclusions</h3><div>The IReAS provides comprehensive data on the diagnosis, genetic subtypes and clinical features of AS patients. It can facilitate genotype-phenotype correlation analyses, offering insights into the AS natural history and potential implications for research on targeted therapies.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"79 ","pages":"Article 105067"},"PeriodicalIF":1.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.ejmg.2025.105064
Ferruccio Romano , Mohammad Sadegh Shams Nosrati , Francesca Madia , Marzia Ognibene , Monica Traverso , Marta Breda , Alireza Dostmohammadi , Marcello Scala , Federico Zara , Maria Margherita Mancardi , Valeria Capra
The Cut Like Homeobox 2 (CUX2) gene encodes a transcription factor critical for neuronal development. Monoallelic pathogenic CUX2 variants are associated with developmental and epileptic encephalopathy 67 (DEE67), an autosomal dominant disorder characterized by variable clinical pictures including early-onset seizures, global developmental delay, and intellectual disability. While most variants described in the literature are missense, only one frameshift variant is reported as likely pathogenic for DEE67 in the ClinVar database. In this study, we report the patient, an 8-year-old girl with clinical features compatible with DEE67, who carries a novel de novo frameshift variant, c.633_636del p.(His211Glnfs∗3), in the CUX2 gene. Although formally classified as a Variant of Uncertain Significance (VUS) based on stringent ACMG criteria, the variant is predicted to be a null allele, likely leading to CUX2 haploinsufficiency via Nonsense-Mediated Decay (NMD). Clinically, her epileptic phenotype consisted of a single generalized tonic-clonic seizure, of milder entity and more treatment-responsive than those of other reported DEE67 cases. This report expands the genotypic spectrum of CUX2-related disorders and provides further evidence supporting haploinsufficiency as a pathogenic mechanism, while describing a milder clinical presentation that broadens the phenotypic spectrum of DEE67.
Cut Like Homeobox 2 （CUX2）基因编码一种对神经元发育至关重要的转录因子。单等位致病CUX2变异与发育性和癫痫性脑病67 （DEE67）有关，DEE67是一种常染色体显性遗传病，其临床表现多样，包括早发性癫痫、全面发育迟缓和智力残疾。虽然文献中描述的大多数变异都是错义的，但在ClinVar数据库中，只有一种移码变异被报道可能是DEE67的致病基因。在这项研究中，我们报告了一名8岁的女孩，其临床特征与DEE67相符，她在CUX2基因中携带一种新的移码变体c.633_636del p.（His211Glnfs∗3）。尽管根据严格的ACMG标准，该变异被正式归类为不确定意义变异（VUS），但该变异被预测为零等位基因，可能通过无义介导的衰变（NMD）导致CUX2单倍体不足。临床，她的癫痫表型包括单一的全身性强直-阵挛性发作，比其他报道的DEE67病例更轻，治疗反应更强。该报告扩大了cux2相关疾病的基因型谱，并提供了进一步的证据支持单倍功能不全是一种致病机制，同时描述了一种较温和的临床表现，拓宽了DEE67的表型谱。
{"title":"A novel frameshift CUX2 variant in a patient with epilepsy and global developmental delay: Phenotypic and genotypic expansion","authors":"Ferruccio Romano , Mohammad Sadegh Shams Nosrati , Francesca Madia , Marzia Ognibene , Monica Traverso , Marta Breda , Alireza Dostmohammadi , Marcello Scala , Federico Zara , Maria Margherita Mancardi , Valeria Capra","doi":"10.1016/j.ejmg.2025.105064","DOIUrl":"10.1016/j.ejmg.2025.105064","url":null,"abstract":"<div><div>The Cut Like Homeobox 2 (<em>CUX2</em>) gene encodes a transcription factor critical for neuronal development. Monoallelic pathogenic <em>CUX2</em> variants are associated with developmental and epileptic encephalopathy 67 (DEE67), an autosomal dominant disorder characterized by variable clinical pictures including early-onset seizures, global developmental delay, and intellectual disability. While most variants described in the literature are missense, only one frameshift variant is reported as likely pathogenic for DEE67 in the ClinVar database. In this study, we report the patient, an 8-year-old girl with clinical features compatible with DEE67, who carries a novel <em>de novo</em> frameshift variant, c.633_636del p.(His211Glnfs∗3), in the <em>CUX2</em> gene. Although formally classified as a Variant of Uncertain Significance (VUS) based on stringent ACMG criteria, the variant is predicted to be a null allele, likely leading to <em>CUX2</em> haploinsufficiency via Nonsense-Mediated Decay (NMD). Clinically, her epileptic phenotype consisted of a single generalized tonic-clonic seizure, of milder entity and more treatment-responsive than those of other reported DEE67 cases. This report expands the genotypic spectrum of CUX2-related disorders and provides further evidence supporting haploinsufficiency as a pathogenic mechanism, while describing a milder clinical presentation that broadens the phenotypic spectrum of DEE67.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"79 ","pages":"Article 105064"},"PeriodicalIF":1.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.ejmg.2025.105031
Alexie Ouellette , Eric P. Allain , Abdullah Almaghraby , Dominique Bouhamdani , Mouna Ben Amor
{"title":"Corrigendum to “A novel RORA genetic variant associated with early-onset obesity and insomnia”","authors":"Alexie Ouellette , Eric P. Allain , Abdullah Almaghraby , Dominique Bouhamdani , Mouna Ben Amor","doi":"10.1016/j.ejmg.2025.105031","DOIUrl":"10.1016/j.ejmg.2025.105031","url":null,"abstract":"","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105031"},"PeriodicalIF":1.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Face2Gene and GestaltMatcher are two artificial intelligence-based tools for facial image analysis and syndrome suggestion.
Material and methods
Frontal photographs of patients (one photograph per patient) with molecularly confirmed diagnosis were uploaded on Face2Gene and GestaltMatcher. The position at which the correct syndrome was listed, and the gestalt scores were noted. The top-3,10 and 30 accuracy was calculated.
Results
A total of 159 patient photographs of 72 different syndromes were analysed. The top-3 accuracy of Face2Gene vs GestaltMatcher was 77 % and 58 % and top-10 accuracy 85 % and 71 % respectively. GestaltMatcher could correctly identify in the top-10 category, 2 out of 7 (28.5 %) monogenic syndromes for which Face2Gene did not have a composite model. Both the tools performed significantly better for rare syndromes as compared to ultrarare syndromes. We also demonstrate through two of our cases the tools’ potential to support variant interpretation in clinical practice.
Conclusion
The combined use of Face2Gene and GestaltMatcher has a considerable potential to support the diagnostic decision process in routine clinical settings.
{"title":"Real-world performance of Face2Gene and GestaltMatcher for facial image analysis in a large Indian ethnic cohort","authors":"Shifali Gupta , Pratibha Bawa , Anu Kumari , Inusha Panigrahi , Priyanka Srivastava , Anupriya Kaur","doi":"10.1016/j.ejmg.2025.105063","DOIUrl":"10.1016/j.ejmg.2025.105063","url":null,"abstract":"<div><h3>Background</h3><div>Face2Gene and GestaltMatcher are two artificial intelligence-based tools for facial image analysis and syndrome suggestion.</div></div><div><h3>Material and methods</h3><div>Frontal photographs of patients (one photograph per patient) with molecularly confirmed diagnosis were uploaded on Face2Gene and GestaltMatcher. The position at which the correct syndrome was listed, and the gestalt scores were noted. The top-3,10 and 30 accuracy was calculated.</div></div><div><h3>Results</h3><div>A total of 159 patient photographs of 72 different syndromes were analysed. The top-3 accuracy of Face2Gene vs GestaltMatcher was 77 % and 58 % and top-10 accuracy 85 % and 71 % respectively. GestaltMatcher could correctly identify in the top-10 category, 2 out of 7 (28.5 %) monogenic syndromes for which Face2Gene did not have a composite model. Both the tools performed significantly better for rare syndromes as compared to ultrarare syndromes. We also demonstrate through two of our cases the tools’ potential to support variant interpretation in clinical practice.</div></div><div><h3>Conclusion</h3><div>The combined use of Face2Gene and GestaltMatcher has a considerable potential to support the diagnostic decision process in routine clinical settings.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105063"},"PeriodicalIF":1.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Occipital encephaloceles are neural tube abnormalities characterized by a median defect of the occipital bone with herniation of brain structures usually contained in a membranous sac. Intracranial structures that protrude range from meninges (meningocele) to cerebral tissue such as occipital lobes, rarely cerebellum, brainstem or torcula.
We present two fetal sibs with occipital meningocele caused by a maternal MSX2 variant identified by whole genome sequencing. Apart from the occipital meningocele, other cerebral abnormalities were found which led to the termination of the two pregnancies. The autopsy confirmed the prenatal findings. Upon clinical examination of the mother, a small scalp defect was discovered consistent with MSX2 gene variant.
To our knowledge, only one case of occipital meningocele caused by MSX2 gene haploinsufficiency has been reported, with maternal inheritance. This paper is aimed at confirming the link between MSX2 gene variant and fetal occipital encephalocele, as well as its clinical variability.
{"title":"Recurrence of occipital meningocele in 2 fetal sibs due to monoallelic MSX2 variant","authors":"Andreea-Catalina Fetecau , Sarah Grotto , Olivia Anselem , Clémence Molac , Jérémy Bertrand , Laurence Lœuillet , Tania Attie-Bitach","doi":"10.1016/j.ejmg.2025.105065","DOIUrl":"10.1016/j.ejmg.2025.105065","url":null,"abstract":"<div><div>Occipital encephaloceles are neural tube abnormalities characterized by a median defect of the occipital bone with herniation of brain structures usually contained in a membranous sac. Intracranial structures that protrude range from meninges (meningocele) to cerebral tissue such as occipital lobes, rarely cerebellum, brainstem or torcula.</div><div>We present two fetal sibs with occipital meningocele caused by a maternal <em>MSX2</em> variant identified by whole genome sequencing. Apart from the occipital meningocele, other cerebral abnormalities were found which led to the termination of the two pregnancies. The autopsy confirmed the prenatal findings. Upon clinical examination of the mother, a small scalp defect was discovered consistent with <em>MSX2</em> gene variant.</div><div>To our knowledge, only one case of occipital meningocele caused by <em>MSX2</em> gene haploinsufficiency has been reported, with maternal inheritance. This paper is aimed at confirming the link between <em>MSX2</em> gene variant and fetal occipital encephalocele, as well as its clinical variability.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"79 ","pages":"Article 105065"},"PeriodicalIF":1.7,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.ejmg.2025.105062
Sophie Giraud , Pascaline Berthet , Caroline Abadie , Nadine Andrieu , Patrick R. Benusiglio , Valérie Bonadona , Olivier Caron , Carole Corsini , Isabelle Coupier , Louise Crivelli , Capucine Delnatte , Pierre Devulder , Antoine DE Pauw , Sophie Dussart , Anne-Paule Gimenez-Roqueplo , Sophie Lejeune-Dumoulin , Jessica Moretta , Marie Muller , Julie Tinat , Stéphane Richard , Nelly Burnichon
Introduction
Renal cancers are inherited in about 5 % of cases and are associated with several genetic syndromes. Genetic testing is recommended for selected patients suspected of having hereditary syndromes. In the absence of guidelines regarding which genes should be included for carrying out genetic screening of these individuals, discrepancies existed among the next generation sequencing (NGS) multi-gene panels (MGP) used in French laboratories. There was therefore a clear need to standardise practices and offer patients with renal cancer a consensus-based genetic testing in France.
Methods
A working group comprising national experts from the French Genetic and Cancer Group Unicancer (GGC) and from the French network on Hereditary PREDIspositions to Renal Cancer (PREDIR) and encompassing medical geneticists, genetic counsellor, molecular biologists and epidemiologists was established. The objective was to define a list of clinically relevant genes that should be included in a “GGC-PREDIR” approved NGS MGP for patients with renal cancer.
A list of 32 genes of interest was compiled following an exhaustive and critical review of the literature. The inclusion or exclusion of each gene was determined based on available data regarding risk, prevalence and analyses published from large studies of patients.
Results
The French group of experts defined a list of 12 genes of clinical and genetic counselling relevance comprising BAP1, FH, FLCN, MET, PTEN, SDHA, SDHB, SDHC, SDHD, TSC1, TSC2 and VHL to be included in the national recommended “renal cancer” NGS MGP. For each of these genes, recommendations for renal surveillance are proposed.
Conclusion
Unlike hereditary predisposition to breast or colon cancer, hereditary renal cancer predispositions are rare syndromes and risk estimates are lacking for most of them. Prospective studies are needed to improve our knowledge.
The GGC-PREDIR experts retained 12 genes for inclusion in the NGS MGP for renal cancer patients. However, the panel will be expanded on the basis of regularly updated data from the medical literature.
{"title":"French recommendations on multi-gene panel testing in renal cell carcinoma","authors":"Sophie Giraud , Pascaline Berthet , Caroline Abadie , Nadine Andrieu , Patrick R. Benusiglio , Valérie Bonadona , Olivier Caron , Carole Corsini , Isabelle Coupier , Louise Crivelli , Capucine Delnatte , Pierre Devulder , Antoine DE Pauw , Sophie Dussart , Anne-Paule Gimenez-Roqueplo , Sophie Lejeune-Dumoulin , Jessica Moretta , Marie Muller , Julie Tinat , Stéphane Richard , Nelly Burnichon","doi":"10.1016/j.ejmg.2025.105062","DOIUrl":"10.1016/j.ejmg.2025.105062","url":null,"abstract":"<div><h3>Introduction</h3><div>Renal cancers are inherited in about 5 % of cases and are associated with several genetic syndromes. Genetic testing is recommended for selected patients suspected of having hereditary syndromes. In the absence of guidelines regarding which genes should be included for carrying out genetic screening of these individuals, discrepancies existed among the next generation sequencing (NGS) multi-gene panels (MGP) used in French laboratories. There was therefore a clear need to standardise practices and offer patients with renal cancer a consensus-based genetic testing in France.</div></div><div><h3>Methods</h3><div>A working group comprising national experts from the French Genetic and Cancer Group Unicancer (GGC) and from the French network on Hereditary PREDIspositions to Renal Cancer (PREDIR) and encompassing medical geneticists, genetic counsellor, molecular biologists and epidemiologists was established. The objective was to define a list of clinically relevant genes that should be included in a “GGC-PREDIR” approved NGS MGP for patients with renal cancer.</div><div>A list of 32 genes of interest was compiled following an exhaustive and critical review of the literature. The inclusion or exclusion of each gene was determined based on available data regarding risk, prevalence and analyses published from large studies of patients.</div></div><div><h3>Results</h3><div>The French group of experts defined a list of 12 genes of clinical and genetic counselling relevance comprising <em>BAP1</em>, <em>FH</em>, <em>FLCN</em>, <em>MET</em>, <em>PTEN</em>, <em>SDHA</em>, <em>SDHB</em>, <em>SDHC</em>, <em>SDHD</em>, <em>TSC1</em>, <em>TSC2</em> and <em>VHL</em> to be included in the national recommended “renal cancer” NGS MGP. For each of these genes, recommendations for renal surveillance are proposed.</div></div><div><h3>Conclusion</h3><div>Unlike hereditary predisposition to breast or colon cancer, hereditary renal cancer predispositions are rare syndromes and risk estimates are lacking for most of them. Prospective studies are needed to improve our knowledge.</div><div>The GGC-PREDIR experts retained 12 genes for inclusion in the NGS MGP for renal cancer patients. However, the panel will be expanded on the basis of regularly updated data from the medical literature.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105062"},"PeriodicalIF":1.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.ejmg.2025.105061
Giorgio Cocchella , Lillian Phung , Elisabeth Wood , Brian Egleston , Lily Hoffman-Andrews , Sarah Brown , Demetrios Ofidis , Rajia Mim , Hannah Griffin , Dominique Fetzer , Anjali Owens , Susan Domchek , Reed Pyeritz , Bryson W. Katona , Staci Kallish , Giorgio Sirugo , JoEllen Weaver , Katherine L. Nathanson , Daniel J. Rader , Angela R. Bradbury
While research participants report interest in receiving genetic research results, how best to return results to ensure medical benefits remains unclear. In the Penn Medicine Biobank Return of Results Study, participants receive results through a digital intervention or a genetic counselor and are recommended to complete clinical confirmation testing and a visit in clinical genetics. We reviewed EHR encounters to understand longitudinal clinical outcomes in 16 patients who completed all steps (Group A), 8 patients who did not complete the clinical genetics visit (Group B), and 21 patients who did not complete confirmation testing or the clinical genetics visit (Group C). Most participants in Group A (69 %) had evidence of adherence to medical recommendations. Some patients faced usual barriers to care and related to comorbid conditions. In contrast, most participants in Group B (75 %) did not have evidence of discussing their confirmed result with a provider or adherence to medical recommendations. Most participants in Group C (71 %) did not have evidence of discussing their research results with providers, although one discussed their unconfirmed result. Men were less likely to complete all steps (Group A), and participants with cardiovascular results were less likely to complete the medical visit (Group B). There was no documentation regarding testing in relatives in any non-genetics encounters for any groups. These data suggest that the steps following return of research results may be critical to realizing the medical benefits of returning actionable genetic research results and highlight the importance of collecting systematic longitudinal outcomes.
{"title":"An electronic review of clinical outcomes after return of actionable genetic research results from a health system research biobank","authors":"Giorgio Cocchella , Lillian Phung , Elisabeth Wood , Brian Egleston , Lily Hoffman-Andrews , Sarah Brown , Demetrios Ofidis , Rajia Mim , Hannah Griffin , Dominique Fetzer , Anjali Owens , Susan Domchek , Reed Pyeritz , Bryson W. Katona , Staci Kallish , Giorgio Sirugo , JoEllen Weaver , Katherine L. Nathanson , Daniel J. Rader , Angela R. Bradbury","doi":"10.1016/j.ejmg.2025.105061","DOIUrl":"10.1016/j.ejmg.2025.105061","url":null,"abstract":"<div><div>While research participants report interest in receiving genetic research results, how best to return results to ensure medical benefits remains unclear. In the Penn Medicine Biobank Return of Results Study, participants receive results through a digital intervention or a genetic counselor and are recommended to complete clinical confirmation testing and a visit in clinical genetics. We reviewed EHR encounters to understand longitudinal clinical outcomes in 16 patients who completed all steps (Group A), 8 patients who did not complete the clinical genetics visit (Group B), and 21 patients who did not complete confirmation testing or the clinical genetics visit (Group C). Most participants in Group A (69 %) had evidence of adherence to medical recommendations. Some patients faced usual barriers to care and related to comorbid conditions. In contrast, most participants in Group B (75 %) did not have evidence of discussing their confirmed result with a provider or adherence to medical recommendations. Most participants in Group C (71 %) did not have evidence of discussing their research results with providers, although one discussed their unconfirmed result. Men were less likely to complete all steps (Group A), and participants with cardiovascular results were less likely to complete the medical visit (Group B). There was no documentation regarding testing in relatives in any non-genetics encounters for any groups. These data suggest that the steps following return of research results may be critical to realizing the medical benefits of returning actionable genetic research results and highlight the importance of collecting systematic longitudinal outcomes.</div></div><div><h3>Clinical trial registration</h3><div>NCT04242667.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105061"},"PeriodicalIF":1.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pathogenic variants in GATA4, a transcription factor, are predominantly associated with congenital heart defects and gonadal abnormalities. We describe a case of a maternally inherited GATA4 pathogenic variant (c.474C > G p.[Tyr158Ter]) in a 21-week gestation fetus presenting with partial atrioventricular septal defect and congenital diaphragmatic hernia. Whilst there is a weight of evidence implicating GATA4 dysfunction in congenital diaphragmatic hernia, this is only the second report to our knowledge to identify a causative GATA4 variant with congenital diaphragmatic hernia.
转录因子GATA4的致病变异主要与先天性心脏缺陷和性腺异常有关。我们描述了一例母体遗传的GATA4致病变异（c.474C> gp .[Tyr158Ter]）在妊娠21周的胎儿表现为部分房室间隔缺损和先天性膈疝。虽然有大量证据表明先天性膈疝中存在GATA4功能障碍，但据我们所知，这只是鉴定先天性膈疝中GATA4致病变异的第二份报告。
{"title":"Pathogenic variant in GATA4 associated with atrioventricular septal defect and congenital diaphragmatic hernia: A case report","authors":"John Howat , Trisha Vigneswaran , Aris Papageorghiou , Sahar Mansour","doi":"10.1016/j.ejmg.2025.105059","DOIUrl":"10.1016/j.ejmg.2025.105059","url":null,"abstract":"<div><div>Pathogenic variants in <em>GATA4</em>, a transcription factor, are predominantly associated with congenital heart defects and gonadal abnormalities. We describe a case of a maternally inherited <em>GATA4</em> pathogenic variant (c.474C > G p.[Tyr158Ter]) in a 21-week gestation fetus presenting with partial atrioventricular septal defect and congenital diaphragmatic hernia. Whilst there is a weight of evidence implicating GATA4 dysfunction in congenital diaphragmatic hernia, this is only the second report to our knowledge to identify a causative <em>GATA4</em> variant with congenital diaphragmatic hernia.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105059"},"PeriodicalIF":1.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.ejmg.2025.105060
Peiqing He , Sini Zou , Jianxiong Chen , Meiyi Wang , Peng Lin , Jiwu Lou , Zhanying Ma , Zhen Li , Tizhen Yan
Pathogenic variants in the NONO gene (MIM #300084) are responsible for X-linked syndromic intellectual developmental disorder-34 (MRXS34, MIM #300967) characterized by macrocephaly, dysmorphic facial features, global developmental delay, hypotonia, heart anomalies, and mild structural brain abnormalities. This report describes a 3-month-old male and a 7-month-old female presenting with microcephaly, dysmorphic facial features, developmental delay, hypotonia, congenital heart defects, abnormal kidney ultrasound, and abnormal cranial MRI findings. The male exhibited left ventricular noncompaction (LVNC), while the female also had abdominal distension and chronic constipation. Whole-exome sequencing (WES) was employed to identify the causative variants. A systematic review of MRXS34 clinical phenotypes was also conducted. WES revealed a novel maternally inherited Xq13.1 hemizygous deletion, encompassing exons 6–13 of the NONO gene in the male, and a recurrent de novo heterozygous c.344G > A (p.Arg115His) variant in NONO in the female. The latter demonstrated extreme X-chromosome inactivation (XCI) skewing. To date, 33 unrelated male cases of MRXS34 have been documented, and 27 NONO variants, have been identified worldwide. The phenotypes in our patients overlap with those previously reported or closely resemble those of MRXS34. Macrocephaly, corpus callosum anomalies, and LVNC exhibit relatively high penetrance but tend to worsen with age. Additionally, dysplastic pulmonary valve/pulmonary hypertension and recurrent chronic constipation episodes may be integral to an alternative NONO-related disorder. This study expands the phenotypic and allelic diversity of NONO-related disorder by providing further genotype-phenotype correlations from two additional cases. The co-occurrence of a NONO variant with extreme XCI skewing likely underpins the pathogenicity of this rare female case, which presents with severe phenotypes akin to those seen in male patients with MRXS34.
NONO基因（MIM #300084）的致病变异是导致x连锁综合征智力发育障碍-34 （MRXS34, MIM #300967）的原因，其特征是大头畸形、面部特征畸形、整体发育迟缓、低紧张、心脏异常和轻度脑结构异常。本报告描述了一个3个月大的男婴和一个7个月大的女婴，表现为小头畸形、面部畸形、发育迟缓、低张力、先天性心脏缺陷、肾脏超声异常和颅脑MRI异常。男性表现为左心室不压实（LVNC），而女性也有腹胀和慢性便秘。采用全外显子组测序（WES）鉴定致病变异。我们还对MRXS34临床表型进行了系统回顾。WES发现了一种新的母系遗传的Xq13.1半合子缺失，包括雄性NONO基因的外显子6-13，以及雌性NONO中复发的新杂合c.344G> a （p.Arg115His）变异。后者表现出极端的x染色体失活（XCI）偏斜。迄今为止，已记录了33例与MRXS34无关的男性病例，并在世界范围内确定了27例NONO变体。我们患者的表型与先前报道的表型重叠或与MRXS34的表型非常相似。巨头畸形、胼胝体异常和LVNC表现出相对较高的外显率，但随着年龄的增长而恶化。此外，肺瓣膜发育不良/肺动脉高压和复发性慢性便秘发作可能是另一种nono相关疾病的组成部分。本研究通过从另外两个病例中提供进一步的基因型-表型相关性，扩展了nono相关疾病的表型和等位基因多样性。NONO变异与极端XCI偏转的共同发生可能支持了这一罕见女性病例的致病性，其表现出与MRXS34男性患者相似的严重表型。
{"title":"Are NONO variants linked to congenital heart disease? Patient reports and review","authors":"Peiqing He , Sini Zou , Jianxiong Chen , Meiyi Wang , Peng Lin , Jiwu Lou , Zhanying Ma , Zhen Li , Tizhen Yan","doi":"10.1016/j.ejmg.2025.105060","DOIUrl":"10.1016/j.ejmg.2025.105060","url":null,"abstract":"<div><div>Pathogenic variants in the <em>NONO</em> gene (MIM #300084) are responsible for X-linked syndromic intellectual developmental disorder-34 (MRXS34, MIM #300967) characterized by macrocephaly, dysmorphic facial features, global developmental delay, hypotonia, heart anomalies, and mild structural brain abnormalities. This report describes a 3-month-old male and a 7-month-old female presenting with microcephaly, dysmorphic facial features, developmental delay, hypotonia, congenital heart defects, abnormal kidney ultrasound, and abnormal cranial MRI findings. The male exhibited left ventricular noncompaction (LVNC), while the female also had abdominal distension and chronic constipation. Whole-exome sequencing (WES) was employed to identify the causative variants. A systematic review of MRXS34 clinical phenotypes was also conducted. WES revealed a novel maternally inherited Xq13.1 hemizygous deletion, encompassing exons 6–13 of the <em>NONO</em> gene in the male, and a recurrent <em>de novo</em> heterozygous c.344G > A (p.Arg115His) variant in <em>NONO</em> in the female. The latter demonstrated extreme X-chromosome inactivation (XCI) skewing. To date, 33 unrelated male cases of MRXS34 have been documented, and 27 <em>NONO</em> variants, have been identified worldwide. The phenotypes in our patients overlap with those previously reported or closely resemble those of MRXS34. Macrocephaly, corpus callosum anomalies, and LVNC exhibit relatively high penetrance but tend to worsen with age. Additionally, dysplastic pulmonary valve/pulmonary hypertension and recurrent chronic constipation episodes may be integral to an alternative <em>NONO</em>-related disorder. This study expands the phenotypic and allelic diversity of <em>NONO</em>-related disorder by providing further genotype-phenotype correlations from two additional cases. The co-occurrence of a <em>NONO</em> variant with extreme XCI skewing likely underpins the pathogenicity of this rare female case, which presents with severe phenotypes akin to those seen in male patients with MRXS34.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105060"},"PeriodicalIF":1.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3.
Clinical report
A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351–1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes.
Results
Exome sequencing identified a heterozygous CLN3 variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989–2025) identified no hematologic abnormalities.
Conclusion
This Japanese CLN3 patient developed visual impairment 7–8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.
{"title":"Persistent lymphopenia in a Japanese boy with neuronal ceroid lipofuscinosis type 3","authors":"Kenta Kajiwara , Qiaowei Liang , Yuri Uchiyama , Pin Fee Chong , Yuko Ichimiya , Norihisa Monji , Sakurako Shimokawa , Motoshi Sonoda , Eriko Watanabe , Ayumi Sakata , Yuri Sonoda , Satoshi Akamine , Masataka Ishimura , Yusuke Murakami , Yuya Kunisaki , Koh-Hei Sonoda , Naomichi Matsumoto , Yasunari Sakai , Shouichi Ohga","doi":"10.1016/j.ejmg.2025.105058","DOIUrl":"10.1016/j.ejmg.2025.105058","url":null,"abstract":"<div><h3>Background</h3><div>Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3.</div></div><div><h3>Clinical report</h3><div>A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351–1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes.</div></div><div><h3>Results</h3><div>Exome sequencing identified a heterozygous <em>CLN3</em> variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989–2025) identified no hematologic abnormalities.</div></div><div><h3>Conclusion</h3><div>This Japanese CLN3 patient developed visual impairment 7–8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105058"},"PeriodicalIF":1.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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