Pub Date : 2026-03-23DOI: 10.1016/j.ejmg.2026.105075
Mohammad Sadegh Shams Nosrati, Ferruccio Romano, Alireza Dostmohammadi, Monica Traverso, Amir Hesam Nemati, Francesca Madia, Patrizia De Marco, Morteza Doustmohammadi, Michele Iacomino, Zahra Hoseini Tavassol, Mahsa Boogari, Reihaneh Khorasanian, Mir Davood Omrani, Federico Zara, Marcello Scala, Valeria Capra
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder caused by biallelic ROBO3 variants, characterized by congenital horizontal gaze restriction, early-onset scoliosis, and distinctive hindbrain malformations. We report two pediatric Patients and integrate current evidence to expand the ROBO3 variant spectrum and refine phenotypic delineation. Detailed clinical evaluation was combined with whole-spine radiography and high-resolution brain MRI with diffusion tensor imaging. Trio-based exome sequencing identified three ROBO3 variants, interpreted according to ACMG/AMP criteria. A novel splice-region variant was evaluated using SpliceAI and Pangolin, while AlphaFold2 modeling and ThermoMPNN, DDMut, SIFT, PolyPhen-2, and ClinPred were used to assess a missense variant affecting the Ig-like domain. Both patients exhibited congenital horizontal gaze palsy, early-onset scoliosis, and the characteristic HGPPS hindbrain triad. Patient #1 carried compound heterozygous variants p.(Arg703Pro) and c.2073+4A>G, while Patient #2 harbored the homozygous p.(Arg245Trp) variant. Literature review confirmed a uniform neuroimaging signature despite variable clinical severity. These findings expand the molecular landscape of HGPPS and underscore the importance of early neuroimaging recognition and orthopedic surveillance in the absence of robust genotype-phenotype correlations.
{"title":"Horizontal gaze palsy with progressive scoliosis (HGPPS): expanding ROBO3 molecular spectrum and refining clinical-neuroimaging phenotypes.","authors":"Mohammad Sadegh Shams Nosrati, Ferruccio Romano, Alireza Dostmohammadi, Monica Traverso, Amir Hesam Nemati, Francesca Madia, Patrizia De Marco, Morteza Doustmohammadi, Michele Iacomino, Zahra Hoseini Tavassol, Mahsa Boogari, Reihaneh Khorasanian, Mir Davood Omrani, Federico Zara, Marcello Scala, Valeria Capra","doi":"10.1016/j.ejmg.2026.105075","DOIUrl":"https://doi.org/10.1016/j.ejmg.2026.105075","url":null,"abstract":"<p><p>Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder caused by biallelic ROBO3 variants, characterized by congenital horizontal gaze restriction, early-onset scoliosis, and distinctive hindbrain malformations. We report two pediatric Patients and integrate current evidence to expand the ROBO3 variant spectrum and refine phenotypic delineation. Detailed clinical evaluation was combined with whole-spine radiography and high-resolution brain MRI with diffusion tensor imaging. Trio-based exome sequencing identified three ROBO3 variants, interpreted according to ACMG/AMP criteria. A novel splice-region variant was evaluated using SpliceAI and Pangolin, while AlphaFold2 modeling and ThermoMPNN, DDMut, SIFT, PolyPhen-2, and ClinPred were used to assess a missense variant affecting the Ig-like domain. Both patients exhibited congenital horizontal gaze palsy, early-onset scoliosis, and the characteristic HGPPS hindbrain triad. Patient #1 carried compound heterozygous variants p.(Arg703Pro) and c.2073+4A>G, while Patient #2 harbored the homozygous p.(Arg245Trp) variant. Literature review confirmed a uniform neuroimaging signature despite variable clinical severity. These findings expand the molecular landscape of HGPPS and underscore the importance of early neuroimaging recognition and orthopedic surveillance in the absence of robust genotype-phenotype correlations.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105075"},"PeriodicalIF":1.7,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510832","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":"2026-03-01","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 : 2026-03-01Epub 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":"<div><div>Cartilage hair hypoplasia (CHH) syndrome (OMIM #<span><span>250250</span><svg><path></path></svg></span>) 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.</div><div>CHH results from homozygous or compound heterozygous mutations in the <em>RMRP</em> gene on chromosome 9p13, which encodes an untranslated RNA component of mitochondrial RNA‐processing endoribonuclease.</div><div><em>RMRP</em> pathogenic variants can also lead to Omenn Syndrome (OS) (OMIM #<span><span>603554</span><svg><path></path></svg></span>), a systemic inflammatory condition displaying neonatal erythroderma and immunodeficiency.</div><div>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.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"80 ","pages":"Article 105069"},"PeriodicalIF":1.7,"publicationDate":"2026-03-01","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}
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":"<div><h3>Background</h3><div>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.</div></div><div><h3>Case presentation</h3><div>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 <em>ACADM</em> 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.</div></div><div><h3>Discussion</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"80 ","pages":"Article 105070"},"PeriodicalIF":1.7,"publicationDate":"2026-03-01","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}
Pub Date : 2026-03-01Epub Date: 2026-02-24DOI: 10.1016/j.ejmg.2026.105071
Cyprian Popescu
Myoclonus–dystonia syndrome (MDS) is an autosomal dominant movement disorder most caused by pathogenic variants in SGCE, an imprinted gene subject to maternal silencing. While numerous pathogenic variants have been reported, the extent and determinants of intrafamilial variability remain incompletely understood. We investigated a large French family in which ten individuals across three generations presented with myoclonic jerks, dystonia, or combined phenotypes. Trio whole-exome sequencing performed in the proband, her affected brother, and her affected father identified a heterozygous SGCE variant, NM_003919.3:c.406T > G, predicting a p.Cys136Gly substitution in a highly conserved cysteine-rich extracellular domain of ε-sarcoglycan. The variant segregated with disease in all clinically affected individuals for whom DNA was available and was absent from population databases. The phenotypic spectrum ranged from mild, stress-induced myoclonus in females to early-onset myoclonus with cervical dystonia and alcohol responsiveness in males, consistent with imprinting effects and sex-dependent modifiers. Variant interpretation using ACMG/AMP criteria (PM1, PM2, PM5, PP1-strong, PP2, PP3) supports a pathogenic classification. This previously unreported SGCE missense variant expands the mutational spectrum of MDS and further illustrates the substantial intrafamilial variability of SGCE-related disease.
{"title":"Intrafamilial variability of myoclonic dystonia in a large French family carrying a novel SGCE variant","authors":"Cyprian Popescu","doi":"10.1016/j.ejmg.2026.105071","DOIUrl":"10.1016/j.ejmg.2026.105071","url":null,"abstract":"<div><div>Myoclonus–dystonia syndrome (MDS) is an autosomal dominant movement disorder most caused by pathogenic variants in SGCE, an imprinted gene subject to maternal silencing. While numerous pathogenic variants have been reported, the extent and determinants of intrafamilial variability remain incompletely understood. We investigated a large French family in which ten individuals across three generations presented with myoclonic jerks, dystonia, or combined phenotypes. Trio whole-exome sequencing performed in the proband, her affected brother, and her affected father identified a heterozygous SGCE variant, NM_003919.3:c.406T > G, predicting a p.Cys136Gly substitution in a highly conserved cysteine-rich extracellular domain of ε-sarcoglycan. The variant segregated with disease in all clinically affected individuals for whom DNA was available and was absent from population databases. The phenotypic spectrum ranged from mild, stress-induced myoclonus in females to early-onset myoclonus with cervical dystonia and alcohol responsiveness in males, consistent with imprinting effects and sex-dependent modifiers. Variant interpretation using ACMG/AMP criteria (PM1, PM2, PM5, PP1-strong, PP2, PP3) supports a pathogenic classification. This previously unreported SGCE missense variant expands the mutational spectrum of MDS and further illustrates the substantial intrafamilial variability of SGCE-related disease.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"80 ","pages":"Article 105071"},"PeriodicalIF":1.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303790","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 : 2026-01-01Epub 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":"2026-01-01","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}
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":"2026-01-01","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 : 2026-01-01Epub Date: 2026-01-10DOI: 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 : 2025-12-01Epub Date: 2025-11-01DOI: 10.1016/j.ejmg.2025.105055
Barbora Lauerova , Radim Mazanec , Katja Eggerman , Dana Safka Brozkova , Annette Lischka , Pavel Seeman , Mikulas Mikula , Petra Lassuthova
Biallelic variants in the FIG4 gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with peripheral neuropathy and central nervous system (CNS) abnormalities, particularly parkinsonism. We aim to extend and specify the phenotype-genotype correlation of the FIG4 variants by presenting four cases of CMT4J, including two with parkinsonism. All patients carried the pathogenic FIG4 variant c.122T > C p.(Ile41Thr) in compound heterozygosity with another variant: c.793C > T p.(Arg265∗), c.498-1G > A, or c.447-2A > C. Disease onset occurred in the first or second decade of life. All presented with demyelinating sensorimotor polyneuropathy, distal muscle weakness of the upper and lower limbs, and foot deformity. In one patient, the muscle weakness was asymmetrical. Two patients developed parkinsonism. Our findings expand the phenotypic spectrum of FIG4-related disorders, reinforcing the link between CMT4J and parkinsonism. These insights are crucial for improving genetic diagnosis and advancing potential therapeutic strategies.
{"title":"Phenotypic spectrum of variants in the FIG4 gene: variants associated with Charcot-Marie-Tooth 4J and parkinsonism","authors":"Barbora Lauerova , Radim Mazanec , Katja Eggerman , Dana Safka Brozkova , Annette Lischka , Pavel Seeman , Mikulas Mikula , Petra Lassuthova","doi":"10.1016/j.ejmg.2025.105055","DOIUrl":"10.1016/j.ejmg.2025.105055","url":null,"abstract":"<div><div>Biallelic variants in the <em>FIG4</em> gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with peripheral neuropathy and central nervous system (CNS) abnormalities, particularly parkinsonism. We aim to extend and specify the phenotype-genotype correlation of the <em>FIG4</em> variants by presenting four cases of CMT4J, including two with parkinsonism. All patients carried the pathogenic <em>FIG4</em> variant c.122T > C p.(Ile41Thr) in compound heterozygosity with another variant: c.793C > T p.(Arg265∗), c.498-1G > A, or c.447-2A > C. Disease onset occurred in the first or second decade of life. All presented with demyelinating sensorimotor polyneuropathy, distal muscle weakness of the upper and lower limbs, and foot deformity. In one patient, the muscle weakness was asymmetrical. Two patients developed parkinsonism. Our findings expand the phenotypic spectrum of <em>FIG4</em>-related disorders, reinforcing the link between CMT4J and parkinsonism. These insights are crucial for improving genetic diagnosis and advancing potential therapeutic strategies.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105055"},"PeriodicalIF":1.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430587","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}
Spinal muscular atrophy (SMA) is a devastating early-onset genetic disease characterized by motor neuron degeneration. For several years, an early access program has facilitated the use of three innovative therapies in France. To better define the therapeutic strategy following innovative therapy approval, an online expert committee within the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) evaluates early diagnosed children and treatment-naive SMA cases during pediatric SMA multidisciplinary team meetings (psMTMs). The decision process leading to molecule choice or palliative care encompasses pretreatment data collection, case presentation during psMTMs, decision support, collective decision-making, and consensus, including the place assigned to parents. The process of setting up a nationwide online network of experts seems to be an effective, reactive and useful procedure in choosing the appropriate therapeutic option for newly diagnosed SMA children.
{"title":"Innovative treatments of pediatric spinal muscular atrophy: The decision-making process in France","authors":"Maelle Biotteau , Juliette Ropars , Brigitte Chabrol , Isabelle Desguerre , Christine Barnéria , Claude Cances","doi":"10.1016/j.ejmg.2025.105044","DOIUrl":"10.1016/j.ejmg.2025.105044","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a devastating early-onset genetic disease characterized by motor neuron degeneration. For several years, an early access program has facilitated the use of three innovative therapies in France. To better define the therapeutic strategy following innovative therapy approval, an online expert committee within the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) evaluates early diagnosed children and treatment-naive SMA cases during pediatric SMA multidisciplinary team meetings (<em>ps</em>MTMs). The decision process leading to molecule choice or palliative care encompasses pretreatment data collection, case presentation during <em>ps</em>MTMs, decision support, collective decision-making, and consensus, including the place assigned to parents. The process of setting up a nationwide online network of experts seems to be an effective, reactive and useful procedure in choosing the appropriate therapeutic option for newly diagnosed SMA children.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105044"},"PeriodicalIF":1.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039508","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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