Molecular Genetics & Genomic Medicine最新文献

{"title":"Genetic Analysis of Pitt-Hopkins Syndrome Caused by a Novel Splicing Variant (c.1146+3A>T) in the TCF4 Gene.","authors":"Wenlong Shen, Yan Zhang, Junjie Wu, Jue Zhao, Yaer Lv, Xiaohua Tang","doi":"10.1002/mgg3.70239","DOIUrl":"10.1002/mgg3.70239","url":null,"abstract":"<p><strong>Objective: </strong>Pitt-Hopkins Syndrome (PTHS) is a rare genetic disorder primarily caused by TCF4 mutations and involves developmental, intellectual, and physical changes in children. Increased nuchal translucency (NT) has not been associated with TCF4 mutations or PTHS. Here we study the connection between increased NT and a c.1146+3A>T mutation in the TCF4 gene.</p><p><strong>Methods: </strong>The genetic basis of increased NT in an early pregnancy fetus was investigated by family trio clinical exome sequencing (CES) using fetal amniotic fluid and parental peripheral blood samples. The candidate variant was validated by Sanger sequencing. The impact of the variant on transcription was assessed using a minigene assay.</p><p><strong>Results: </strong>Early ultrasound revealed an NT measurement of 3.5 mm in fetus B of a twin pregnancy. CES identified a de novo heterozygous c.1146+3A>T variant in intron 14 of TCF4, confirmed by Sanger sequencing. In vitro minigene experiments showed that the mutation disrupted TCF4 mRNA splicing, resulting in exon 14 skipping and a truncated transcript.</p><p><strong>Conclusion: </strong>Our results identified c.1146+3A>T as a novel splicing variant of the TCF4. The TCF4 c.1146+3A>T mutation may underlie increased NT in early pregnancy, suggesting that increased NT could be an early intrauterine sign of PTHS.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70239"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Rare Clinical Presentation of Variegate Porphyria.","authors":"I Viakhireva, A Murtazina, A Orlova, N Makretskaya, S Nikitin, M Skoblov","doi":"10.1002/mgg3.70243","DOIUrl":"10.1002/mgg3.70243","url":null,"abstract":"<p><strong>Background: </strong>Variegate porphyria is a rare heme biosynthesis disorder caused by pathogenic variants in the PPOX gene. Despite being relatively well characterized, its clinical manifestations are highly variable and can mimic a broad spectrum of neurological and systemic conditions.</p><p><strong>Case presentation: </strong>We report the case of a young woman with recurrent episodes of muscle weakness, sometimes accompanied by respiratory dysfunction. Initially suspected to have myasthenia gravis, laboratory testing for this condition was negative. Whole-genome sequencing identified a heterozygous pathogenic variant c.338G>C in the PPOX gene and a homozygous variant of uncertain significance c.190G>A in MYMK, with no other disease-causing variants detected in genes associated with congenital myasthenic syndromes or periodic paralysis.</p><p><strong>Conclusion: </strong>In the described case, the patient's atypical clinical manifestations led to a prolonged and complex diagnostic workup. WGS findings suggested possible co-occurrence of variegate porphyria with a potential overlap with a Carey-Fineman-Ziter syndrome. This case highlights the importance of comprehensive evaluation of the clinical presentation in patients with unexplained neuromuscular symptoms.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70243"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Approach to Interrogating Whole Genome Sequencing Data to Optimise Clinical Utility.","authors":"Sarah Sonner, Caoimhe McKenna, Shirley Heggarty, Cassie Hamill, Cheryl Flanagan, Shane McKee, Katie Kerr, Rasha Alhazzaa, Amy Jayne McKnight, Fionnuala Mone","doi":"10.1002/mgg3.70248","DOIUrl":"10.1002/mgg3.70248","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the performance of the genomic analytics applied to the Northern Ireland cohort recruited to the 100,000 Genomes Project, focusing on diagnostic yields in first-line analysis and revisiting inconclusive cases with rare diseases.</p><p><strong>Methods: </strong>Whole genome sequencing (WGS) and initial data processing were performed centrally by Genomics England (GEL), consistent with a national protocol. A novel internal approach to variant selection and interpretation was designed using a two-pronged pathway; with initial prioritisation using GEL virtual panels and subsequent Exomiser-mediated reanalysis of remaining undiagnosed cases. Retrospective collection of genomic records was completed for service evaluation.</p><p><strong>Results: </strong>Of 440 patients recruited 20.2% (n = 89/440) received a monogenic diagnosis; 69.7% (n = 62/89) via the initial interpretation pathway (analysed between 2019 and 2021) and 30.3% (n = 27/89) via the secondary pathway (analysed between 2019 and 2025). The majority of variants missed by the initial analysis were because the diagnostic gene was not included as a target on the applied panel(s) at the time of analysis. The median turnaround time for the initial approach was 644.5 days (range: 315-1342) and for the secondary approach was 1766.5 days (range: 862-2311). The secondary approach was found to be more effective in prioritising pathogenic variants; 69.7% (n = 62/89) versus 89.9% (n = 80/89) p = 0.0008.</p><p><strong>Conclusion: </strong>Pre-classification variant selection and reanalysis of undiagnosed cases are critical to optimise quality improvement in the clinical delivery of WGS. Variant selection via virtual panels can expedite interpretation but may miss clinically relevant findings, leaving cases undiagnosed. Revisiting these cases gave an additional ~6% yield. For efficient variant selection in both initial and follow-up analysis, a multi-disciplinary approach is required.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70248"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYO6 and Heart: A Novel Variant in a Deaf Infant With Supraventricular Tachycardia.","authors":"Samira Kalayinia, Tannaz Masoumi, Amirreza Taherkhani, Nejat Mahdieh, Mohammadrafie Khorgami, Majid Maleki","doi":"10.1002/mgg3.70244","DOIUrl":"10.1002/mgg3.70244","url":null,"abstract":"<p><strong>Background: </strong>Variants in MYO6 are well known causes of hereditary deafness and have occasionally been linked to cardiac abnormalities, including hypertrophic cardiomyopathy and prolonged QT interval. However, supraventricular tachycardia (SVT) has not previously been associated with this gene.</p><p><strong>Aim: </strong>To describe a neonate with congenital deafness, paroxysmal SVT, and QT prolongation carrying a novel homozygous MYO6 variant.</p><p><strong>Methods: </strong>A 2-month-old male infant with bilateral congenital sensorineural hearing loss presented with recurrent paroxysmal SVT. Clinical evaluation included ECG, Holter monitoring, echocardiography, and laboratory studies. Whole-exome sequencing followed by Sanger validation was performed to identify genetic alterations.</p><p><strong>Results: </strong>The infant experienced repeated SVT episodes responsive to adenosine and was noted to have a prolonged QTc interval of 569 ms in sinus rhythm. Echocardiography showed mild LV enlargement with preserved function and no structural anomalies. Genetic testing revealed a novel homozygous frameshift variant in MYO6 (c.2496_2497delAC; p.H833Qfs*5).</p><p><strong>Conclusion: </strong>While causality cannot be confirmed, this observation raises the possibility that MYO6 dysfunction may contribute to arrhythmogenic susceptibility in addition to its established role in auditory function. Further studies are warranted to clarify the relationship between MYO6 variants and cardiac conduction abnormalities.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70244"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13243183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148199539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: LncRNA NEAT1/mir-185-5p/igf2 Axis Regulates the Invasion and Migration of Colon Cancer.","authors":"","doi":"10.1002/mgg3.70247","DOIUrl":"10.1002/mgg3.70247","url":null,"abstract":"<p><strong>Retraction: </strong>S. Zhuang, Y. Cai, H. Liu, Y. Qin, and J. Wen, \"LncRNA NEAT1/mir-185-5p/igf2 Axis Regulates the Invasion and Migration of Colon Cancer,\" Molecular Genetics & Genomic Medicine 8, no. 4 (2020): e1125, https://doi.org/10.1002/mgg3.1125. The above article, published online on 20 February 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Paraminder Dhillon; and Wiley Periodicals, LLC. The retraction has been agreed due to concerns raised by third parties. Specifically, image elements in Figures 1D, 3D, 3E, 4G, and 5C were identified as having been published elsewhere in a different scientific context. As a result, the editors consider the conclusions to be invalid. The authors were unable to adequately address these concerns, noting that, due to the time elapsed since the original publication, retrieval of the underlying raw data for verification would be difficult. The authors therefore requested the retraction of the article.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70247"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Genetic Characterization of Inherited NPRL3 Splice Variants in Two Patients With Epilepsy.","authors":"Shouxing Wang, Jihua Wu, Conglei Song, Yuanzhi He, Zhongli Zhao, Bin Yang","doi":"10.1002/mgg3.70240","DOIUrl":"10.1002/mgg3.70240","url":null,"abstract":"<p><strong>Background: </strong>NPRL3-related epilepsy (NRE) is a GATORopathy characterized by focal seizures, with or without focal cortical dysplasia. Although NPRL3 variants have been associated with syndromes such as familial focal epilepsy with variable foci and sleep-related hypermotor epilepsy, the genotype-phenotype correlations in NRE remain poorly understood. This study aimed to investigate the clinical and genetic features of NRE in two Chinese families, together with a review of the genotype-phenotype spectrum.</p><p><strong>Methods: </strong>Two pediatric Chinese patients with NRE were identified through whole-exome sequencing (WES). Clinical, neuroimaging, laboratory, and genetic data were analyzed. A review of reported NRE cases was conducted.</p><p><strong>Results: </strong>Inherited NPRL3 splice variants (NM_001077350.3: c.924 + 1G>A and c.925-1G>C) were identified in both probands using WES; both were inherited from their asymptomatic mothers. The patients presented with seizures starting at 1-2 years of age. Proband 1 experienced focal and focal to bilateral tonic-clonic seizures (FBTCS), while Proband 2 had focal seizures. Neuroimaging findings were normal. Patient 1 achieved seizure control with sodium valproate, oxcarbazepine, and lacosamide, while Patient 2 responded to oxcarbazepine and levetiracetam. A literature review of 41 articles identified 94 NPRL3 variants in 84 pedigrees and 23 cohort cases with epilepsy, revealing an estimated penetrance of 76% (162/214). Loss-of-function variants predominated (83%), while splice variants were relatively rare (13%). No clear genotype-phenotype correlations were observed, even in cases with identical NPRL3 variants.</p><p><strong>Conclusion: </strong>The findings of the study highlight the genetic and clinical heterogeneity of NRE, which is characterized by incomplete penetrance and phenotypic variability. This underscores the importance of tailored antiepileptic management and the consideration of NPRL3 variants as causes of familial and sporadic epilepsy.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70240"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review.","authors":"Yang Xiu, Yige Zhang, Yake Jiao, Wei Wang, Yanyan Hu","doi":"10.1002/mgg3.70251","DOIUrl":"10.1002/mgg3.70251","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To report the clinical manifestations and genetic diagnosis of a female patient with X-linked intellectual developmental disorder-93 (XLID93, OMIM#300659) caused by a BRWD3 gene mutation. Systematically summarize the clinical and genetic characteristics of reported female cases and analyze the genotype-phenotype correlation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A case of XLID93 in a 1-year-and-3-month-old girl was reported. Perform whole-exome sequencing, qPCR copy number verification, X-chromosome inactivation analysis, and three-dimensional protein structure prediction for the child in this case; systematically search relevant databases, and summarize and analyze the phenotypes and genotypes of 5 female patients with BRWD3 mutations reported in the literature to date.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The patient was a 1-year-and-3-month-old female presenting with delayed gross motor development, unable to stand or walk independently; poor fine motor skills; high muscle tone in the upper limbs and low muscle tone in the lower limbs. Her head circumference was 48.2 cm (95th-97th). She had slightly wide eye spacing, a low nasal bridge, a prominent forehead, a short neck, and a low posterior hairline. There was a heterozygous deletion variation of exon (loss1, EXON 21-30) in the BRWD3 gene of the patient. First-generation verification showed that both parents of the proband were wild-type; this mutation is a de novo mutation, and it is currently impossible to determine whether it is located on the paternal or maternal X chromosome. Protein structure prediction shows that this deletion results in the complete loss of a bromodomain, which may significantly affect the protein function. Through X-chromosome inactivation testing, the inactivation ratio of the maternally derived X-chromosome of the proband was about 89%, indicating non-random inactivation. In summary, the analysis of the clinical and genetic characteristics of five female patients with XLID93 syndrome caused by BRWD3 gene mutations shows that their core clinical phenotypes have obvious commonalities, mainly manifested as: developmental delay (60%), neurological manifestations (60%), head circumference greater than the 95th percentile (60%), and special facial features (40%), with the overall clinical manifestations being milder than those in the male population. Notably, all three female patients who underwent X chromosome inactivation (XCI) testing exhibited skewed XCI, and the severity of the clinical phenotype was closely related to the direction and degree of XCI skewing: patients with preferential inactivation of the mutant X chromosome had milder clinical manifestations (patient 1 had mild cognitive impairment in early childhood); in contrast, patients with preferential inactivation of the normal X chromosome and active expression of the mutant X chromosome had more severe phenotypes (patient 4 had macrocephaly, special facial features, and developmental de","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70251"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13269170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A c.89G>C p.(Gly30Ala) Variant in the DHCR7 Gene as a Cause of a Mild Phenotype in the Smith-Lemli-Opitz Syndrome.","authors":"Júlia Martinková, Emílie Vyhnálková, Martin Schwarz, Miroslava Balaščaková, Veronika Biddle, Romana Borská, Lenka Fajkusová, Lukáš Ryba, Anna Křepelová","doi":"10.1002/mgg3.70222","DOIUrl":"10.1002/mgg3.70222","url":null,"abstract":"<p><strong>Background: </strong>Smith-Lemli-Opitz syndrome (SLOS) is a common autosomal recessive disorder caused by pathogenic variants in the DHCR7 gene, resulting in a deficiency of the enzyme 7-dehydrocholesterol reductase. Two forms of SLOS are recognized based on the severity of associated symptoms. Type I is characterized by a milder phenotype, whereas type II is more severe and frequently results in fetal loss or early neonatal death. We observed two unrelated patients: a 5-year-old boy and a 3.5-year-old girl, with elevated 7-DHC levels, a milder phenotype, and an identical genotype.</p><p><strong>Methods: </strong>Variants were confirmed by Sanger sequencing.</p><p><strong>Results: </strong>A rare heterozygous likely pathogenic variant, c.89G>C p.(Gly30Ala), and a pathogenic variant, c.964-1G>C, in the trans position in the DHCR7 gene were identified in both patients.</p><p><strong>Conclusion: </strong>The two unique patients presented here suggest that the c.89G>C p.(Gly30Ala) variant is associated with a mild SLOS phenotype, which may be overlooked and unrecognized in clinical practice. Information about this rare DHCR7 variant is important for diagnostic awareness of SLOS, especially within the Central European population. We present clinical data and a literature review of the DHCR7 variants associated with the mild SLOS phenotype.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70222"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13581065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Transcriptome Analysis of Intrauterine UPD6pat Fetuses With Distinct Phenotypes.","authors":"Jiahui Yu, Yan Zhang, Wenlong Shen, Jun Ying, Huanzheng Li, Xiaohua Tang, Xujun He","doi":"10.1002/mgg3.70241","DOIUrl":"10.1002/mgg3.70241","url":null,"abstract":"<p><strong>Objective: </strong>Uniparental disomy of chromosome 6, typically paternal in origin (UPD6pat), results in significant phenotypic variability across different cases. This study integrates transcriptome-wide profiling of amniotic fluid cell-free RNA (cfRNA) with molecular diagnostics to elucidate the gene expression landscape and pathway dysregulation in two phenotypically distinct UPD6pat cases.</p><p><strong>Methods: </strong>RNA sequencing (RNA-seq) was performed on amniotic fluid supernatants from two UPD6pat fetuses and two gestational age-matched controls.</p><p><strong>Results: </strong>Differential expression analysis revealed 372 significantly dysregulated genes (242 upregulated and 130 downregulated; p < 0.05, |logFC| ≥ 0.5) enriched in pathways related to glucose metabolism, neurodegenerative diseases, and cellular processes. Gene set enrichment analysis (GSEA) further highlighted UPD6pat-associated perturbations in type 1 diabetes and glycosylphosphatidylinositol biosynthesis pathways. Phenotype-specific analysis revealed opposing expression trends in growth restriction genes and clubfoot-related genes (EP300 and CHD7), with protein-protein interaction (PPI) networks implicating epigenetic modulation and cytoskeletal dynamics as potential drivers of phenotypic divergence.</p><p><strong>Conclusion: </strong>Despite limitations in sample size, our findings underscore the utility of amniotic fluid cfRNA analysis as a noninvasive tool for prenatal diagnostics and highlight novel targets for further functional validation.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70241"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic Refinement of ESAM-Related Tight-Junctionopathy: Novel Genetic and Ocular Findings and Literature Review.","authors":"Mauro Lecca, Chiara Bosetti, Federico Ruoli, Liviana Fontanel, Marco Mazza, Enza Maria Valente, Roberta Battini, Edoardo Errichiello","doi":"10.1002/mgg3.70245","DOIUrl":"10.1002/mgg3.70245","url":null,"abstract":"<p><strong>Background: </strong>Endothelial cell-selective adhesion molecule (ESAM) is a tight junction protein essential for blood-brain barrier integrity and angiogenesis. Bi-allelic loss-of-function variants in ESAM cause NEDIHSS (\"Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity\"), a neurodevelopmental/neurovascular disorder with antenatal/neonatal onset, characterized by global developmental delay/intellectual disability (GDD/ID), epilepsy, spasticity, ventriculomegaly, and intracranial hemorrhages. Ocular involvement, particularly retinal vascular anomalies, has been variably reported.</p><p><strong>Methods: </strong>A multidisciplinary team of pediatric neurologists, ophthalmologists, and clinical geneticists evaluated the proband through clinical assessment, neuro/ocular imaging, and whole-exome sequencing.</p><p><strong>Results: </strong>We describe a 3-year-old male from consanguineous Albanian parents carrying a novel homozygous splice-site ESAM variant (c.70+1G>T). He presented with GDD, seizures, and brain imaging abnormalities consistent with NEDIHSS. Remarkably, bilateral optic nerve hypoplasia, esotropia, retinal detachment, absent electroretinogram response, and structural eye anomalies, including left eyeball hypoplasia and iris displacement, were observed. Review of our and previous cases indicates that 45% (10/22) of NEDIHSS individuals present ocular manifestations, mainly retinal vascular defects, reinforcing the emerging role of ESAM in retinal endothelial integrity.</p><p><strong>Conclusions: </strong>This case broadens the mutational and clinical spectrum of ESAM-related disease, underscores the need for detailed ocular evaluations in NEDIHSS, and supports inclusion of retinal anomalies within its core phenotype.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 6","pages":"e70245"},"PeriodicalIF":1.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}