Pub Date : 2026-01-28DOI: 10.1016/j.ejmg.2026.105069
Anna Insalaco, Cecilia Rossi, Emma Bertucci, Chiara Fiorentini, Annarosa Soresina, Silvia Giliani, Fulvio Porta, Alberto Berardi, Licia Lugli
Cartilage hair hypoplasia (CHH) syndrome (OMIM #250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hypotrichosis and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases, and predisposition to malignancies. CHH results from homozygous or compound heterozygous mutations in the RMRP gene on chromosome 9p13, which encodes an untranslated RNA component of mitochondrial RNA-processing endoribonuclease. RMRP pathogenic variants can also lead to Omenn Syndrome (OS) (OMIM #603554), a systemic inflammatory condition displaying neonatal erythroderma and immunodeficiency. This report highlights the genotypic and phenotypic overlap between CHH and OS, by presenting a newborn with skeletal dysplasia, immunodeficiency and neonatal onset erythroderma, carrying the homozygous NR_003051:n.35C > A variant in the RMRP gene.
{"title":"Neonatal erythroderma and immunodysplasia: Overlap of cartilage-hair hypoplasia and Omenn syndrome.","authors":"Anna Insalaco, Cecilia Rossi, Emma Bertucci, Chiara Fiorentini, Annarosa Soresina, Silvia Giliani, Fulvio Porta, Alberto Berardi, Licia Lugli","doi":"10.1016/j.ejmg.2026.105069","DOIUrl":"10.1016/j.ejmg.2026.105069","url":null,"abstract":"<p><p>Cartilage hair hypoplasia (CHH) syndrome (OMIM #250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hypotrichosis and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases, and predisposition to malignancies. CHH results from homozygous or compound heterozygous mutations in the RMRP gene on chromosome 9p13, which encodes an untranslated RNA component of mitochondrial RNA-processing endoribonuclease. RMRP pathogenic variants can also lead to Omenn Syndrome (OS) (OMIM #603554), a systemic inflammatory condition displaying neonatal erythroderma and immunodeficiency. This report highlights the genotypic and phenotypic overlap between CHH and OS, by presenting a newborn with skeletal dysplasia, immunodeficiency and neonatal onset erythroderma, carrying the homozygous NR_003051:n.35C > A variant in the RMRP gene.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105069"},"PeriodicalIF":1.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092544","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}
Background: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management.
Case presentation: We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A > C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours.
Discussion: This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available.
Conclusions: Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.
背景：中链酰基辅酶a脱氢酶缺乏症（MCADD）是欧洲最常见的脂肪酸氧化障碍。临床发病通常发生在3至24个月之间，伴有低酮性低血糖症，而新生儿表现较少见。虽然该疾病典型表现为代谢性失代偿，但非典型心脏累及偶有报道，但仍极为罕见。MCADD被包括在许多新生儿筛查项目中，从而实现早期发现和及时管理。病例介绍：我们报告了一个足月女性新生儿，在出生3天后，出现了严重的代谢性失代偿，并伴有难治性室上性心动过速，严重的收缩功能障碍和双室扩张，需要最大的肌力支持。扩大的新生儿筛查显示了与MCADD一致的特征，基因检测发现了ACADM基因的纯合变异，根据HGVS命名为ACADM(NM_000016.6):c。985 C > p。(Lys329Gln)。疾病特异性治疗，包括高速率静脉注射葡萄糖、补充肉碱和量身定制的低脂饮食，可在48小时内使心功能完全正常化。讨论：本病例表现为新生儿发病的MCADD的速心肌病样表现，这是一种新颖且很少被描述的心脏表型。它强调了在新生儿不明原因心律失常和心肌病的鉴别诊断中考虑脂肪酸氧化障碍的重要性，特别是在新生儿筛查结果可用之前。结论：早期诊断和及时开始代谢治疗对于逆转MCADD可能危及生命的心脏表现至关重要。本报告强调了一种新的表型，扩大了新生儿发病MCADD的临床谱。
{"title":"Tachycardiomyopathy-like presentation in neonatal MCAD deficiency: A novel cardiac phenotype.","authors":"Elisabetta Morana, Federico Baronio, Marcello Lanari, Egidio Candela, Rita Ortolano, Simone Bonetti, Gabriele Bronzetti, Giacomo Biasucci, Tammam Hasan, Luca Ragni, Andrea Donti","doi":"10.1016/j.ejmg.2026.105070","DOIUrl":"10.1016/j.ejmg.2026.105070","url":null,"abstract":"<p><strong>Background: </strong>Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management.</p><p><strong>Case presentation: </strong>We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A > C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours.</p><p><strong>Discussion: </strong>This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available.</p><p><strong>Conclusions: </strong>Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105070"},"PeriodicalIF":1.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084925","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}
Paediatric cancer predisposing factors (CPFs), such as DICER1 syndrome, Li-Fraumeni syndrome, and SMARC-related syndromes, are increasingly being identified through genome-wide sequencing of surgical specimens. Among these, mutations in the SWItch/Sucrose Non-Fermentable chromatin-remodelling complex, particularly involving the SMARCE1 gene, have been implicated in various paediatric tumours, including clear cell meningioma (CCM). However, the role of SMARCE1 mutations in other rare tumours like chordoma remains undetermined. TBXT is a gain-of-function driver mutation of chordoma alongside upregulated transforming growth factor beta 1 (TGFβ1) and epidermal growth factor receptor (EGFR). Herein, we report a rare case of thoracic chordoma with sudden abdominal pain after treatment for intracranial CCM. Germline analyses of surgical specimens from CCM and chordoma showed heterozygous mutations in both the SMARCE1 (chromosome 17q21.2) and TBXT (brachyury, chromosome 6q27) genes. Somatic mutation analyses showed loss of heterozygosity at the SMARCE1 gene region in both CCM and chordoma surgical specimens, as well as at the TBXT gene region in CCM, but not in chordoma. We speculated that both TBXT and SMARCE1 might indirectly promote EGFR signalling to drive chordoma cell proliferation and survival, although the direct interaction between TBXT and SMARCE1 is unknown. To our knowledge, this is the first report of a patient with a spinal chordoma after CCM treatment, suggesting that SMARCE1 is a candidate pathological factor in chordoma.
{"title":"Thoracic chordoma following intracranial meningioma in a patient with a novel germline SMARCE1 variant","authors":"Takao Tsurubuchi , Yuni Yamaki , Hiroko Fukushima , Kosuke Sato , Hiroshi Takahashi , Hiroki Karita , Noriaki Sakamoto , Masashi Mizumoto , Kei Nakai , Hideyuki Sakurai , Ai Muroi , Masahide Matsuda , Hidetoshi Takada , Eiichi Ishikawa","doi":"10.1016/j.ejmg.2026.105068","DOIUrl":"10.1016/j.ejmg.2026.105068","url":null,"abstract":"<div><div>Paediatric cancer predisposing factors (CPFs), such as DICER1 syndrome, Li-Fraumeni syndrome, and SMARC-related syndromes, are increasingly being identified through genome-wide sequencing of surgical specimens. Among these, mutations in the SWItch/Sucrose Non-Fermentable chromatin-remodelling complex, particularly involving the <em>SMARCE1</em> gene, have been implicated in various paediatric tumours, including clear cell meningioma (CCM). However, the role of <em>SMARCE1</em> mutations in other rare tumours like chordoma remains undetermined. <em>TBXT</em> is a gain-of-function driver mutation of chordoma alongside upregulated <em>transforming growth factor beta 1</em> (<em>TGFβ1</em>) and <em>epidermal growth factor receptor</em> (<em>EGFR</em>). Herein, we report a rare case of thoracic chordoma with sudden abdominal pain after treatment for intracranial CCM. Germline analyses of surgical specimens from CCM and chordoma showed heterozygous mutations in both the <em>SMARCE1</em> (chromosome 17q21.2) and <em>TBXT</em> (brachyury, chromosome 6q27) genes. Somatic mutation analyses showed loss of heterozygosity at the <em>SMARCE1</em> gene region in both CCM and chordoma surgical specimens, as well as at the <em>TBXT</em> gene region in CCM, but not in chordoma. We speculated that both <em>TBXT</em> and <em>SMARCE1</em> might indirectly promote <em>EGFR</em> signalling to drive chordoma cell proliferation and survival, although the direct interaction between <em>TBXT</em> and <em>SMARCE1</em> is unknown. To our knowledge, this is the first report of a patient with a spinal chordoma after CCM treatment, suggesting that <em>SMARCE1</em> is a candidate pathological factor in chordoma.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"80 ","pages":"Article 105068"},"PeriodicalIF":1.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994297","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 : 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}
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