American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献_第2页

Milestone Attainment in Young Children With Arthrogryposis Multiplex Congenita: Developmental Profile and Associated Factors. 幼儿多重先天性关节挛缩的里程碑成就：发展概况和相关因素。

IF 4.4 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2026-03-16 DOI: 10.1002/ajmg.c.70006

Ahlam Zidan, Sophia C Pasia, Emmanouil Rampakakis, Reggie Hamdy, Frank Rauch, Lauren C Hyer, Joel Lerman, Haluk Altiok, Krister Freese, Cary Mielke, Sarah B Nossov, Philip F Giampietro, Thania Ordaz-Robles, Noémi Dahan-Oliel

{"title":"Milestone Attainment in Young Children With Arthrogryposis Multiplex Congenita: Developmental Profile and Associated Factors.","authors":"Ahlam Zidan, Sophia C Pasia, Emmanouil Rampakakis, Reggie Hamdy, Frank Rauch, Lauren C Hyer, Joel Lerman, Haluk Altiok, Krister Freese, Cary Mielke, Sarah B Nossov, Philip F Giampietro, Thania Ordaz-Robles, Noémi Dahan-Oliel","doi":"10.1002/ajmg.c.70006","DOIUrl":"https://doi.org/10.1002/ajmg.c.70006","url":null,"abstract":"Evidence on developmental milestones in children with arthrogryposis multiplex congenita (AMC) under the age of five is scarce. This multisite cross-sectional study described developmental status and examined factors associated with milestone attainment in 143 children aged 0-66 months from a pediatric AMC Registry. Development was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3), across Communication, Gross Motor, Fine Motor, Problem-Solving, and Personal-Social domains. Independent variables included demographic, perinatal, clinical, and parental factors. Gross Motor function was the most limited domain, with more than 90% scoring close to/below the ASQ-3 domain-specific cutoff (≥ 2 SD below normative mean). Personal-Social scores were unexpectedly low, and Fine Motor limitations were also frequent, with 53.1% scoring close to/below the cutoff. Communication and Problem-Solving were relative strengths. Longer neonatal intensive-care unit stays were linked to poorer Communication and Fine Motor scores, and higher birth weight was associated with better Problem-Solving performance. Specific joint contractures, particularly those affecting the neck, shoulder, elbow, and knee, were associated with lower performance across domains, while higher parental education was related to better Personal-Social outcomes. Developmental attainment in AMC is shaped by interactions among musculoskeletal, perinatal, and family factors, underscoring the importance of early, coordinated orthopedic, developmental and family-centered interventions.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prenatal Evaluation of RNU4-2 Variants in Fetuses With Central Nervous System Anomalies. 中枢神经系统异常胎儿RNU4-2变异的产前评估

IF 4.4 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-25 DOI: 10.1002/ajmgc.70002

Yiyao Chen, Li Gao, Xu Han, Yunyun Cao, Lanlan Zhang, Yi Wu, Xinrong Zhao, Wenjing Hu, Ruiyu Ma, Renyi Hua, Niu Li, Yanlin Wang, Jian Wang, Shuyuan Li

{"title":"Prenatal Evaluation of RNU4-2 Variants in Fetuses With Central Nervous System Anomalies.","authors":"Yiyao Chen, Li Gao, Xu Han, Yunyun Cao, Lanlan Zhang, Yi Wu, Xinrong Zhao, Wenjing Hu, Ruiyu Ma, Renyi Hua, Niu Li, Yanlin Wang, Jian Wang, Shuyuan Li","doi":"10.1002/ajmgc.70002","DOIUrl":"10.1002/ajmgc.70002","url":null,"abstract":"Fetal central nervous system (CNS) anomalies are among the most common congenital malformations, yet the overall prenatal diagnostic yield of current genetic testing remains below 40%. Variants in RNU4-2, a non-coding gene encoding the U4 small nuclear RNA (snRNA), have recently been linked to a novel highly recurrent dominant neurodevelopmental disorder termed ReNU syndrome. While its postnatal phenotype has been well characterized, the contribution of RNU4-2 to fetal CNS anomalies remains unexplored. In this study, we retrospectively analyzed 148 fetuses with CNS anomalies who had non-diagnostic results from karyotyping, chromosomal microarray analysis, and exome sequencing. Targeted Sanger sequencing of RNU4-2 was performed to identify pathogenic variants. Two fetuses harbored the same de novo recurrent variant, n.64_65insT, corresponding to a diagnostic yield of 1.35%. Both cases presented with microcephaly, suggesting that it is a key prenatal feature of ReNU syndrome. Furthermore, molecular confirmation of RNU4-2 resolved a decade-long diagnostic odyssey in one family by excluding an inherited Xp22.13 duplication of uncertain significance as the causal variant. In conclusion, this study provides the first systematic prenatal evaluation of RNU4-2 in fetuses with CNS anomalies, thereby expanding the prenatal phenotypic spectrum of ReNU syndrome. Incorporating RNU4-2 testing into prenatal genetic workflows may enhance diagnostic yield, enable precise genetic counseling, and support informed reproductive decision-making.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Descriptive Epidemiology From the Myhre Syndrome Foundation Registry: The Value of Self-Reported Data. 来自Myhre综合征基金会登记处的描述性流行病学：自我报告数据的价值。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2025-11-11 DOI: 10.1002/ajmg.c.32159

Mary K Young, Armelle Pindon, Maggie R Brand, Kate Wears, Katherine H Young, Alyssa Mendel, Michael J Lyons

引用次数: 0

Unraveling the Mechanistic Spectrum of Myhre Syndrome: SMAD4 Signaling Disruption, Skeletal Phenotypes, and Translational Innovation. 揭示Myhre综合征的机制谱：SMAD4信号中断，骨骼表型和转化创新。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2026-02-08 DOI: 10.1002/ajmgc.70004

Min Zhu, Fanyuan Zeng, Chu Zhu

{"title":"Unraveling the Mechanistic Spectrum of Myhre Syndrome: SMAD4 Signaling Disruption, Skeletal Phenotypes, and Translational Innovation.","authors":"Min Zhu, Fanyuan Zeng, Chu Zhu","doi":"10.1002/ajmgc.70004","DOIUrl":"10.1002/ajmgc.70004","url":null,"abstract":"Myhre syndrome (MYHRS) is an ultra-rare, progressive multisystem disorder caused by recurrent heterozygous missense variants in the SMAD4 gene, a central mediator of TGF-β and BMP signaling. Skeletal abnormalities-including postnatal short stature, brachydactyly, thickened calvarium, and craniofacial dysmorphism-are cardinal features, often accompanied by joint contractures and progressive soft tissue fibrosis. Extensive cellular and genetic evidence supports a gain-of-function (GoF) mechanism wherein mutant SMAD4 displays increased protein stability and prolonged nuclear localization, enhancing canonical SMAD signaling and driving overexpression of profibrotic and extracellular matrix (ECM) genes. Although a dominant-negative (DN) effect was recently proposed for some variants, GoF remains the prevailing and best-supported model. The underlying skeletal pathophysiology likely reflects both primary disruption of mesenchymal differentiation affecting bone and cartilage, and secondary progressive fibrosis that amplifies contractures and skeletal rigidity over time, though direct mechanistic studies in bone tissue remain limited. Therapeutically, TGF-β pathway inhibitors such as losartan exhibit promising in vitro and early clinical benefits, while advanced strategies-spanning targeted small molecules, anti-fibrotic agents, and emerging gene-editing approaches-are prospective direction for therapies. The integration of patient-derived iPSC models engineered animal systems, multi-modal technologies, and artificial intelligence (AI) holds significant promise for precision medicine in Myhre syndrome.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"344-358"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Review of the Molecular and Developmental Basis of Myhre Syndrome, Bench Research. Myhre综合征的分子和发育基础综述，基础研究。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2026-06-10 DOI: 10.1002/ajmg.c.70010

Camille Viaut, Valerie Cormier-Daire

{"title":"Review of the Molecular and Developmental Basis of Myhre Syndrome, Bench Research.","authors":"Camille Viaut, Valerie Cormier-Daire","doi":"10.1002/ajmg.c.70010","DOIUrl":"10.1002/ajmg.c.70010","url":null,"abstract":"Myhre syndrome (MS) is a connective-tissue disorder within the acromelic dysplasia spectrum. It is characterized by congenital craniofacial, skeletal, cutaneous anomalies, respiratory, cardiovascular along with intellectual disability, deafness, and progressive fibrosis. MS is caused by germline variants in the transcriptional co-regulator SMAD4 (mothers against DPP homolog 4). SMAD4 is a key intracellular mediator of signal transduction and participates in several pathways, notably canonical TGFβ and BMP signaling. These pathways play central roles in developmental and homeostatic processes. As the number of reported MS cases continues to grow, clarifying its pathophysiology is becoming increasingly important. Current evidence suggests that dysregulation of TGFβ/BMP signaling contributes to extracellular matrix (ECM) disorganization and fibrosis in MS, a relationship that remains under active investigation. Here, we review the literature and summarize current knowledge on the clinical features and pathogenic mechanisms of MS. We also discuss emerging biological roles of molecular actors that appear to be compromised, and outline therapeutic strategies that may lead to promising interventions to improve patients' quality of life.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"405-413"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Research Review of Myhre Syndrome. Myhre综合征的研究综述。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2025-06-06 DOI: 10.1002/ajmg.c.32145

Maggie R Brand, Ryan Monsberger, Robert J Hopkin, Angela E Lin

引用次数: 0

I Breathed. 我呼吸。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2026-08-28 DOI: 10.1002/ajmg.c.70019

Patti M Schultz

引用次数: 0

Cardio-Respiratory Complications in Adult Monozygotic Twins With Myhre Syndrome. Myhre综合征成年同卵双胞胎的心肺并发症。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2025-08-17 DOI: 10.1002/ajmg.c.32150

Hyoungjun Sim, Forrest Wilke, Emily Hamburger, Charlie J Sang, Clara Hildebrandt

{"title":"Cardio-Respiratory Complications in Adult Monozygotic Twins With Myhre Syndrome.","authors":"Hyoungjun Sim, Forrest Wilke, Emily Hamburger, Charlie J Sang, Clara Hildebrandt","doi":"10.1002/ajmg.c.32150","DOIUrl":"10.1002/ajmg.c.32150","url":null,"abstract":"Myhre syndrome is a rare connective tissue disorder characterized by skeletal, cardiopulmonary, dermatologic, neurocognitive changes, and a predisposition to exaggerated fibrosis in response to mechanical stress. We report monozygotic male twins with Myhre syndrome caused by the recurrent SMAD4 gain-of-function variant c.1498A>G (p.Ile500Val), identified by targeted next-generation sequencing of peripheral blood. Proband 1 presented at age 37 years for evaluation of symptomatic aortic stenosis. Clinical recognition of Myhre syndrome prompted deferral of transesophageal echocardiography, and molecular diagnosis informed subsequent conservative management. His co-twin, Proband 2, underwent posterior pharyngeal flap surgery and right-heart catheterization with pulmonary artery stenting in childhood; later, he developed progressive pulmonary arterial hypertension and died at 31 years. We report on the differing outcomes of the twins and the possibility that invasive airway and cardiac procedures may have accelerated fibro-proliferative complications of Proband 2. Early recognition of Myhre syndrome allows selection of alternatives to high-risk procedures, longitudinal monitoring, and may reduce morbidity and mortality.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"283-289"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Detailed Autopsies Performed on Two Females With Myhre Syndrome Elucidate Features of SMAD4 Gain-of-Function Pathophysiology. 对两名患有Myhre综合征的女性进行的详细尸检阐明了SMAD4功能获得的病理生理特征。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2025-12-03 DOI: 10.1002/ajmg.c.32158

Katelyn Dannheim, Grant Eilers, Nathan C Page, Shipra Garg, Kelsie Anderson, Elizabeth Colglazier, Claire Parker, David F Teitel, Henry C Sanchez, Ryan Sidebottom, Brandon Abbott, Jasmine L Knoll, Maggie R Brand, Hongmei Mou, Mark E Lindsay, Angela E Lin

{"title":"Detailed Autopsies Performed on Two Females With Myhre Syndrome Elucidate Features of SMAD4 Gain-of-Function Pathophysiology.","authors":"Katelyn Dannheim, Grant Eilers, Nathan C Page, Shipra Garg, Kelsie Anderson, Elizabeth Colglazier, Claire Parker, David F Teitel, Henry C Sanchez, Ryan Sidebottom, Brandon Abbott, Jasmine L Knoll, Maggie R Brand, Hongmei Mou, Mark E Lindsay, Angela E Lin","doi":"10.1002/ajmg.c.32158","DOIUrl":"10.1002/ajmg.c.32158","url":null,"abstract":"Pathologic studies of Myhre syndrome (OMIM 139201) have provided modest insights into this ultra-rare multisystem disorder, with postmortem examinations being scarce. Morbidity is related to severe congenital heart defects, aortic hypoplasia, airway stenosis, constrictive pericarditis, and restrictive cardiomyopathy. We report two detailed autopsies: the first of an 8-year-old female who succumbed to congenital mitral valve disease and restrictive cardiopulmonary complications. Autopsy documented chronic pericarditis and fibrosing pleuritis, diffuse interstitial pulmonary fibrosis, extensive submucosal interstitial fibrosis of the bladder, and nodular medial hypertrophy of the aorta. The second patient was a 20-year-old female with progressive laryngo-tracheal stenosis, interstitial lung disease, pericardial and peritoneal adhesions, and dermal fibrosis. Both patients had ovarian fibrosis with reduced oocytes. Neuropathologic examination revealed brains below expected weight with hypoxic-ischemic injury. The first patient also had scattered intraparenchymal microcalcifications and a known Chiari I malformation, and the second had a thickened calvarium and dura mater and rounded cerebrum (shortened frontal and occipital lobes). These two patients demonstrate the value of postmortem examination to confirm suspected pathology and elucidate new features. The pleiotropy of Myhre syndrome was demonstrated by complex comorbidities and the devastating impact of indiscriminate fibrosis. Counseling regarding the role of postmortem examination should be considered in the palliative care of Myhre syndrome patients and their families.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"313-329"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Review of Cutaneous Manifestations in Myhre Syndrome With Histopathological Analyses and Genotype-Phenotype Correlation. Myhre综合征皮肤表现与组织病理学分析和基因型-表型相关性的综述。

IF 2.5 3区医学

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Pub Date : 2025-12-01 Epub Date: 2026-02-12 DOI: 10.1002/ajmgc.70005

Setu Mittal, Emma F Johnson, Lisa A Schimmenti, Nessa Aghazadeh Mohandesi

{"title":"Review of Cutaneous Manifestations in Myhre Syndrome With Histopathological Analyses and Genotype-Phenotype Correlation.","authors":"Setu Mittal, Emma F Johnson, Lisa A Schimmenti, Nessa Aghazadeh Mohandesi","doi":"10.1002/ajmgc.70005","DOIUrl":"10.1002/ajmgc.70005","url":null,"abstract":"Myhre syndrome is a rare multisystem disorder characterized by distinctive facial features, hearing loss, and progressive fibrosis affecting the skin, joints, lungs, and cardiovascular system. It is caused by heterozygous pathogenic variants in the SMAD4 gene. In this review, we detail the cutaneous manifestations observed in two previously reported patients with genetically confirmed Myhre syndrome. While skin biopsies demonstrated pan-dermal thickening of collagen bundles, the immunohistochemical staining patterns were distinct from those seen in other inflammatory sclerosing disorders. Additionally, we conducted a comprehensive literature review of the cutaneous features associated with Myhre syndrome, identifying 175 patients with confirmed SMAD4 pathogenic variants. The most reported cutaneous finding was thickened or stiff skin (76%), followed by keratosis pilaris (22%) and impaired wound healing or abnormal scarring (18%). Genotype-phenotype analysis suggested a diagnostic delay in patients with the codon 496 variant, who were more frequently diagnosed in adulthood. This variant may also be associated with a milder cutaneous phenotype, highlighting the clinical heterogeneity of Myhre syndrome. These findings underscore the importance of recognizing cutaneous features as potential early diagnostic clues in patients with suspected Myhre syndrome.","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"359-370"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0