American Journal of Medical Genetics Part A最新文献

{"title":"Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and TBX4-FGF10 Signaling Pathways.","authors":"Katarzyna Bzdęga, Gail H Deutsch, Małgorzata Rydzanicz, Witold Błaż, Elżbieta Rafińska-Ważny, Anna P Terpin, Dariia Klepach, Valentyna Zakharova, Rafał Płoski, Tomasz Szczapa, Justyna A Karolak","doi":"10.1002/ajmg.a.64071","DOIUrl":"https://doi.org/10.1002/ajmg.a.64071","url":null,"abstract":"<p><p>Lethal lung developmental disorders (LLDDs), histologically classified as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), congenital alveolar dysplasia (CAD), acinar dysplasia (AcDys), and primary pulmonary hypoplasia (PH), are rare diseases associated with high neonatal mortality due to refractory respiratory failure. Although ACDMPV mostly results from single nucleotide variants (SNVs) or copy-number variants (CNVs) involving FOXF1, AcDys, CAD, and PH are often associated with abnormalities within TBX4 or FGF10. These genes interact in the SHH-FOXF1 and TBX4-FGF10 signaling network and are known regulators of lung development. Recent studies conducted in TBX4-, FGF10-, or FOXF1-deficient LLDD lungs revealed decreased expression of TMEM100 at the transcriptomic and immunohistochemical levels. Here, we present four new patients with genetically and histopathologically confirmed LLDD, including ACDMPV (n = 2), AcDys (n = 1), and PH (n = 1), in whom we detected a heterozygous variants involving FOXF1 (n = 2) or TBX4 (n = 2). Additional immunohistochemical (TMEM100) and qPCR analyses (TMEM100, TBX4, FOXF1) performed in lung tissues of these newborns revealed a significant reduction in TMEM100, TBX4, and FOXF1 expression. Our results confirm previous findings indicating the possible involvement of TMEM100 in FOXF1-TBX4-FGF10 molecular signaling that, when disrupted, may lead to LLDD.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64071"},"PeriodicalIF":1.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Update on 3M Syndrome: Review of Clinical and Molecular Aspects and Report of Additional Families.","authors":"Shaymaa Elsayed, Gehad A Elmakkawy, Ibrahim M Abdelrazek, Dina A Fawzy, JiHye Kim, YongJun Song, Omneya M Omar, Ebtesam M Abdalla","doi":"10.1002/ajmg.a.64068","DOIUrl":"https://doi.org/10.1002/ajmg.a.64068","url":null,"abstract":"<p><p>3M syndrome is a rare autosomal recessive disorder characterized by short stature and recognizable facial and musculoskeletal features. Pathogenic variants in the CUL7, OBSL1, and CCDC8 genes are implicated in the pathogenesis of 3M syndrome. In this review, we discuss the history, epidemiology, molecular basis, clinical features, and management strategies for 3M syndrome. Moreover, we report on 11 new patients (from 9 unrelated families) with short stature and dysmorphic features consistent with 3M syndrome, in whom we identified five novel pathogenic variants expanding the genetic landscape of the syndrome. Finally, we have reviewed the molecularly confirmed cases of 3M published to date.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64068"},"PeriodicalIF":1.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Tyrosine Kinase Domain of CSF1R? A Case Report From an Adult-Onset Leukoencephalopathy.","authors":"Piervito Lopriore, Gianmichele Migaleddu, Pei-Chien Tsai, Antonella Fogli, Maria Adelaide Caligo, Gabriele Siciliano, Mirco Cosottini, Yi-Chung Lee, Yi-Chu Liao, Michelangelo Mancuso, Roberto Ceravolo, Daniela Frosini","doi":"10.1002/ajmg.a.64065","DOIUrl":"https://doi.org/10.1002/ajmg.a.64065","url":null,"abstract":"<p><p>Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also termed hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1), results from mutations in the CSF1R gene and leads to progressive leukoencephalopathy. This autosomal dominant condition typically manifests in the fourth or fifth decade of life with a combination of early-onset dementia, neuropsychiatric changes, and motor symptoms. CSF1R mutations are predominantly located within the tyrosine kinase domain (TKD) of the protein, crucial for its kinase activity. However, variants outside the TKD can also disrupt kinase function. Here, we report a 58-year-old man with early-onset dementia and a novel missense variant [c.1735C>G, p.(Arg579Gly)] just outside the TKD of CSF1R. Functional analysis showed impaired autophosphorylation of the mutant protein, supporting its pathogenicity. This case highlights the importance of functional validation in newly identified CSF1R variants, underscoring the need for comprehensive genetic and functional analysis in diagnosing and understanding this rare neurological disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64065"},"PeriodicalIF":1.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Phenotypic Spectrum of DPH2-Related Disorder.","authors":"Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Uddhava V Kinhal, Sahana M Srinivas, Himani Pandey, Nagaraja M Phani, Pavithra Dhayalan, Devi Lal","doi":"10.1002/ajmg.a.64061","DOIUrl":"https://doi.org/10.1002/ajmg.a.64061","url":null,"abstract":"<p><p>Biallelic variants in DPH2 have recently been reported to cause the syndrome of developmental delay with short stature, dysmorphic facial features, and sparse hair-2, also known as diphthamide deficiency syndrome-2. Here we report a child with a biallelic loss-of-function variant p.(Arg477*) in DPH2 with clinical features of developmental delay, failure to thrive, sparse hair, seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. The electroencephalogram was suggestive of modified hypsarrhythmia. The phenotype of the current case overlaps with the previous cases reported in the literature; however, seizures, behavioral issues, and neuroimaging abnormalities have not been reported to date. This is the third report from the world. The current report gives a detailed account of an Indian child with a DPH2-related disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64061"},"PeriodicalIF":1.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous Pathogenic Variants in SERPINB7 Potentially Associated With Concomitant Moyamoya Angiopathy and Nagashima-Type Palmoplantar Keratoderma.","authors":"Lilia Kazerooni, Benjamin N Vogel, Abhik K Banerjee, Saba Jafarpour, Jonathan D Santoro","doi":"10.1002/ajmg.a.64058","DOIUrl":"https://doi.org/10.1002/ajmg.a.64058","url":null,"abstract":"<p><p>The authors present the first documented case of concomitant Nagashima-type palmoplantar keratoderma and moyamoya angiopathy, identifying a novel gene as a potential link between rare dermatologic and cerebrovascular diseases. The subject of this case report was identified and clinically evaluated at the Neurological Institute of Children's Hospital Los Angeles. Written informed consent for clinical care, genetic testing, and participation in this case study was obtained. The patient initially presented with a history of several dermatologic conditions, including eczema, vitiligo, and Nagashima-type palmoplantar keratoderma. Neurological examination and diagnostic imaging were strongly suggestive of moyamoya angiopathy, prompting a bilateral encephaloduroarteriomyosynangiosis. Singleton Clinical Exome Sequencing was subsequently performed, revealing pathogenic heterozygous variants in SERPINB7. This study identifies SERPINB7 as a possible link between Nagashima-type palmoplantar keratoderma and moyamoya angiopathy, indicating the pleomorphism of SERPINB7-mediated changes in human disease. Further studies are warranted to investigate the function of SERPINB7 in endovascular tissue. Furthermore, the increasingly recognized association between autoimmune dermatologic disease and moyamoya may be mediated through genetic mechanisms, highlighting the importance of genetic testing in individuals with rare dermatologic and cerebrovascular disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64058"},"PeriodicalIF":1.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Heterozygous c.1024A>G Variant in BMPR1B Causes Either Isolated Brachydactyly Type A4 With Variable Expressivity or Incomplete Type A4 Overlapping Type D in a Chinese Han Pedigree.","authors":"Xinyi Yang, Xiaqing Wu, Hua Li, Runji Zhou, Kai Guo, Chunping Shang, Songhua Zhao, Mingyi Ma","doi":"10.1002/ajmg.a.64060","DOIUrl":"https://doi.org/10.1002/ajmg.a.64060","url":null,"abstract":"<p><p>BDA4 and BDD are rare autosomal dominant conditions characterized by distinct hand/foot malformations, including middle phalangeal shortening in the second and fifth digits and short, broad thumb terminal phalanges. While variations in BMPR1B have been implicated in the pathogenesis of BDA1 and BDA2, the genetic basis underlying BDA4 and BDD remains unclear. Clinical and radiographic phenotyping were performed to assess and diagnose the affected pedigree. Whole-exome sequencing and Sanger sequencing were employed to identify and validate the genetic variation. Bioinformatics analyses were conducted to evaluate the potential pathogenicity of the variant. Functional validation was carried out by assessing SMAD4 localization in BMP4-stimulated 293T transfectants. We present the first report of a rare Chinese Han pedigree exhibiting two distinct phenotypes: isolated BDA4 and incomplete BDA4 overlapping BDD, which were observed across two branches. All affected individuals harbored a novel heterozygous c.1024A>G (p.K342E) variant in BMPR1B, with bioinformatics analyses suggesting its pathogenic potential. Structural analyses indicated a conformational change within the kinase domain. Functional assays revealed a marked reduction in nuclear SMAD4 accumulation in transfectants expressing the mutant BMPR1B compared to the wild-type counterpart. This study provides the first evidence implicating BMPR1B as a pathogenic gene for both isolated BDA4 and incomplete BDA4 with BDD overlap. The BMPR1B c.1024A>G (p.K342E) variant disrupts kinase activity and impairs SMAD1/5/8 phosphorylation, which in turn suppresses downstream IHH expression and interferes with BMP-mediated skeletal patterning. We propose that the variant, in combination with genetic background and environmental factors, leads to the observed variable expressivity in this pedigree. Our findings expand the mutational spectrum of brachydactyly and underscore BMPR1B as a candidate gene for further investigation in brachydactyly pathogenesis.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64060"},"PeriodicalIF":1.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LARS2-Related Perrault Syndrome in Siblings With 46,XY Differences of Sex Development.","authors":"Aaron P Adam, Lauren O'Sullivan, Amanda Peterson, Megan Yabumoto, Paul Merguerian, Margaret P Adam","doi":"10.1002/ajmg.a.64064","DOIUrl":"https://doi.org/10.1002/ajmg.a.64064","url":null,"abstract":"<p><p>Perrault syndrome is a heterogeneous phenotype that generally encompasses the findings of sensorineural hearing loss in both 46,XX and 46,XY individuals and varying degrees of abnormal ovarian function in 46,XX individuals. In this case report, we present two brothers with LARS2-related Perrault syndrome who have undervirilization. In addition to bilateral profound sensorineural hearing loss, both brothers had bilateral undescended testes that required surgical intervention. In addition, the younger affected brother had hypospadias with chordee. Quad exome sequencing on both brothers was consistent with 46,XY and revealed the same biallelic pathogenic variants in LARS2, a gene known to be associated with Perrault syndrome. No other variants were reported on exome analysis. To date, undervirilization in 46,XY individuals who have Perrault syndrome has only rarely been reported, although the number of reported males with Perrault syndrome continues to be small. Pathogenic variants in LARS2 have been found to lead to ovarian dysgenesis in 46,XX individuals and complete infertility due to failure to produce germ cells in Caenorhabditis elegans (C. elegans), indicating that LARS2 is expressed in gonadal tissue and can impact gonadal development. Undervirilization in affected males is likely an underrecognized component of the LARS2-related Perrault syndrome. In this article, we suggest that LARS2 be included in the differential diagnosis of both 46,XX and 46,XY individuals with DSD conditions and should be considered in 46,XY individuals with hearing loss and evidence of undervirilization.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64064"},"PeriodicalIF":1.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity Prevalence in DDX3X-Related Neurodevelopmental Disorder.","authors":"Giavanna Verdi, Nathaniel H Robin","doi":"10.1002/ajmg.a.64062","DOIUrl":"https://doi.org/10.1002/ajmg.a.64062","url":null,"abstract":"<p><p>The purpose of this study is to analyze the prevalence of obesity in those affected by DDX3X-related neurodevelopmental disorder (DDX3X-NDD). Initial descriptions suggested that individuals with DDX3X-NDD suffered from poor weight gain or failure to thrive in early childhood, likely in the setting of feeding difficulties and secondary to associated hypotonia. However, through a patient's parent, we came to learn that obesity was a common problem for older patients. To investigate this, we developed a survey to be distributed to caregivers of patients with DDX3X-NDD. The flyer contained a QR code to access an online and anonymous survey, with questions regarding the diagnosis of DDX3X-NDD and concerns about obesity in the affected child. Approximately 31% of the study population (n = 70) expressed concerns about obesity on the anonymous survey, and nearly half of this population found obesity to be a concern after the diagnosis of DDX3X-NDD. Common interventions that were implemented for obesity concerns included medications, visits with Endocrinology specialists, exercise regimens, and diet modifications. There is not a defined correlation between concerns for obesity and other medical diagnoses affecting this clinical symptom prevalence, since it is understood that autism can affect diet and weight. The degree of intellectual disability in those with obesity concerns and diagnoses of DDX3X-NDD was not established. Our findings suggest that while poor weight gain due to feeding difficulties in infancy is common, obesity is a common health concern for older DDX3X-NDD patients.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64062"},"PeriodicalIF":1.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Costello Syndrome and Ophthalmologic Issues: Unveiling the Unseen.","authors":"Sofia Peschiaroli, Germana Viscogliosi, Annabella Salerni, Emanuele Crincoli, Roberta Mattei, Tommaso Verdolotti, Serafina Antonella Loprete, Valentina Trevisan, Giovanni Antonio Marrocco, Alessia Cherubino, Lucrezia Perri, Roberta Onesimo, Giuseppe Zampino, Chiara Leoni","doi":"10.1002/ajmg.a.64049","DOIUrl":"https://doi.org/10.1002/ajmg.a.64049","url":null,"abstract":"<p><p>Costello syndrome (CS) is an ultra-rare condition belonging to the RASopathies, a group of disorders characterized by aberrant RAS/MAPK pathway signaling, which is involved in ocular development and in some eye pathologies. However, only a few studies assessing the ophthalmic features of individuals with CS are available. In this article, we describe the main ophthalmic anomalies and MRI findings in a large cohort of CS patients and compare our data with theliterature. 21 individuals with CS were enrolled and performedvisual acuity and refractive error assessment, intraocular pressure (IOP) evaluation, ocular motility examination, anterior segment inspection, fundus examination, macular optical coherence and corneal tomography, and brain MRI with the measurement of optic nerve thickness. A high prevalence of refractive errors was observed (90%), amblyopia, with best-corrected visual acuity below 20/40 in at least one eye in all assessed cases. Strabismus was also described in the present cohort (95%), with exotropia, esotropia, and hypertropia equally present. Moreover, 66.7% of our patients presented nystagmus. OCT was normal in all cases performed (6). Eighteen individuals underwent brain MRI, and 63% of them showed an altered optic nerve thickness. We described for the first time to date bilateral optic nerve thickness reduction assessed through MRI in CS. Moreover, in our cohort, we detect a high prevalence of amblyopia, refractive errors, and nystagmus across all ages. These findings support the implementation of an early ophthalmologic assessment and management in patients with CS to prevent deterioration of visual functions; therefore, improving overall quality of life.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64049"},"PeriodicalIF":1.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pilot Study to Evaluate Neurodevelopmental Outcomes in a Pediatric Cohort With Genodermatoses.","authors":"Sneha A Rangu, Kierstin Keller, Dong Li, Hope Thomas, Nora O'Connor, Abbas F Jawad, Allison Thomas, Nina H Thomas, Hakon Hakonarson, Leslie Castelo-Soccio, Sarah E Sheppard","doi":"10.1002/ajmg.a.63989","DOIUrl":"https://doi.org/10.1002/ajmg.a.63989","url":null,"abstract":"<p><p>Our study aimed to evaluate cognitive function in individuals with genetic skin disorders involving neuroectoderm (n = 8) compared to individuals with only ectoderm or mesoderm (n = 16) involvement. We hypothesized that neuroectodermal involvement would result in poorer neurocognitive performance. A prospective, cross-sectional pilot study of 24 participants evaluated cognition, adaptive skills, behavior, and quality of life (QoL) using neurodevelopmental tests. Participants' characteristics and outcomes of interest were summarized by standard descriptive statistics using means, standard deviation, median, and 95% confidence intervals. We found no differences between mean cognitive composite standard score, adaptive composite standard score, QoL raw score, or internalizing and externalizing behavior T-scores between the neuroectodermal group (82.3, 90.3, 70.3, and 50.0, respectively; average age = 7 years) and the ectodermal/mesodermal group (87.8, 96.4, 80.4, and 54.3, respectively; average age = 5.9 years). No differences were seen in neurodevelopmental functioning between both groups. Our pilot study presents a framework for utilizing neurocognitive testing in patients with genodermatoses. A limitation of our work is the high level of heterogeneity due to varying diagnoses seen in each group requiring larger sample sizes for determination of clinical significance. Future work is needed to include homogenous diagnoses and to evaluate the most efficacious interventions to maximize neurodevelopmental outcomes in individuals with genodermatoses.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63989"},"PeriodicalIF":1.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}