American Journal of Medical Genetics Part A最新文献

{"title":"On the Path to Pediatric Genetics: Reflections From Future Clinicians.","authors":"Claire M Kittock, Rachel H Ceron, Kochakorn Buasri, Christy Capestany, Selena Vanapruks, Megan F Baxter, Luke Plaisted, Kayley Anderson, Meredith Fuchs, Anusha Vavilikolanu, Jillian Shapiro, Fatima Tokhmafshan, Luciana D Garlisi-Torales","doi":"10.1002/ajmg.a.70189","DOIUrl":"10.1002/ajmg.a.70189","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2586-2589"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175271","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":"Novel Homozygous Exonic Deletion of the TMEM17 Gene Associated With Meckel-Gruber Syndrome Phenotype.","authors":"Inusha Panigrahi, Sneha Sagarkar, Udhaya Kotecha, Vasundhara Tamhankar, Parag M Tamhankar","doi":"10.1002/ajmg.a.70227","DOIUrl":"10.1002/ajmg.a.70227","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2581-2585"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262821","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":"Report of a Homozygous Nonsense Variant in the WDR91 Gene Associated With Severe Communicating Hydrocephalus, Dandy Walker Malformation, and Cerebellar Hypoplasia.","authors":"Rhea Shriyan, Tushar Kachhadiya, Rishi Sharma, Shwetal Patel, Salil Vaniawala, Vasundhara P Tamhankar, Pramila Menon, Shalin Vaniawala, Shilpa Mithbawkar, Parag M Tamhankar","doi":"10.1002/ajmg.a.70228","DOIUrl":"10.1002/ajmg.a.70228","url":null,"abstract":"<p><p>The WDR81 and WDR91 genes are important for endosome conversion, fusion, recycling, and transport. Variants in the WDR81 gene have been reported in human patients with cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome type 2 (CAMRQ2, MIM #610185) and in patients with congenital hydrocephalus with brain anomalies type 3 (HYC3, MIM #617967). Both phenotypes are transmitted in an autosomal recessive inheritance pattern. Loss-of-function type variants in the WDR91 gene have also been recently described in patients with brain malformations such as hydrocephalus, brain atrophy, corpus callosum agenesis, micro-lissencephaly, and cerebellar hypoplasia. However, the literature is scarce, and this association has not been cataloged in the Online Mendelian Inheritance in Man (OMIM) database. Herein, we report a novel homozygous nonsense variant in the WDR91 gene in a child with severe congenital communicating hydrocephalus, Dandy-Walker malformation (not described before in association with this gene), cerebellum hypoplasia, and facial dysmorphism. Exome sequencing (trio) revealed a novel homozygous variant c.1245_1246delAG (transcript ID NM_014149.4) in the WDR91 gene predicted to lead to premature termination variant p.(Arg415Serfs*64). The variant was confirmed on Sanger sequencing in the proband and the asymptomatic parents were shown to be heterozygous for the same variant, demonstrating autosomal recessive inheritance. A review of medical literature revealed that in mice, global Wdr91 knockout causes neonatal death, whereas brain-specific Wdr91 inactivation impairs brain development and causes marked neuronal loss in the cerebrum and cerebellum. We show that as per the Clingen guidelines for gene-disease assertion, the evidence for loss-of-function variants in the WDR91 gene leading to congenital hydrocephalus is strong and supports its inclusion in the OMIM database.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2562-2567"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269913","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":"Abnormal Presentation of FGFR2-Related Bent Bones Dysplasia Surviving Past the Perinatal Period in the United States.","authors":"Sara Hill, Nathaniel H Robin, Christopher Fowler, Joseph B Philips","doi":"10.1002/ajmg.a.70221","DOIUrl":"10.1002/ajmg.a.70221","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2590-2591"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300697","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":"Re: \"Clinical Insights From a Case of Sifrim-Hitz-Weiss Syndrome With a CHD4 Variant: Expanding the Phenotypic Spectrum and Its Response to Growth Hormone Therapy\".","authors":"Himanshu Goel","doi":"10.1002/ajmg.a.70229","DOIUrl":"10.1002/ajmg.a.70229","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2592-2593"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306728","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":"MYH11-Related Hereditary Type 2 Visceral Myopathy in a Large Kindred: Diagnostic Odyssey With Milder Clinical Manifestations.","authors":"Jai Kumar Rajavoor Muniswamy, Elise Van Zele, Ali Agely, Karthik Muthusamy","doi":"10.1002/ajmg.a.70235","DOIUrl":"10.1002/ajmg.a.70235","url":null,"abstract":"<p><p>MYH11-related hereditary type 2 visceral myopathy is a rare smooth muscle disorder typically presenting in infancy with severe gastrointestinal and genitourinary dysfunction. We describe a 73-year-old female with lifelong symptoms of gastrointestinal and urinary dysfunction, including chronic constipation, neurogenic bladder, recurrent urinary tract infections, gastroparesis, and pelvic organ prolapse. A multigenerational family history revealed similar visceral smooth muscle abnormalities among 14 affected individuals over five generations, suggesting autosomal dominant inheritance. Whole-genome sequencing identified a heterozygous, likely pathogenic variant in MYH11 c.5819del; p.(Pro1940HisfsTer91), consistent with the diagnosis of autosomal dominant type 2 visceral myopathy. This variant causes production of an abnormally elongated myosin-heavy chain, disrupting muscle contractile function. This individual's survival into her eighth decade reflects long-term clinical stability, possibly attributable to the variant's milder effect. We describe the clinical course of the disease, along with a comprehensive review of previously described individuals with the same variant. This case broadens the phenotypic spectrum of MYH11-associated visceral myopathy, demonstrating that late-onset, milder forms can occur and remain compatible with long-term survival with optimal supportive management. Comprehensive genetic evaluation identifies primary disorders, enabling precise diagnosis, tailored management, and informed genetic counseling for complex phenotypes.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2575-2580"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337214","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":"Severe ADEM-Like Neuroinflammatory Disease and Cerebrovascular Fragility With Recurrent Pseudoaneurysms and Moyamoya in a Familial Germline CBL Mutation: Expanding the Clinical Phenotype.","authors":"Michal Bar-Hakim, Anat Abramovich, Sara Via-Dorembus, Gali Heimer, Bruria Ben-Zeev, Etai Adam, Assaf A Barg, Jonathan Roth, Basheer Sheick-Yousif, Rony Beeri Berkowiz, Michal Feldon, Haim Bassan, Moran Hausman-Kedem","doi":"10.1002/ajmg.a.70232","DOIUrl":"10.1002/ajmg.a.70232","url":null,"abstract":"<p><p>Heterozygous germline variants in CBL disrupt its function as a negative regulator of the Ras/MAPK pathway, classically predisposing to Juvenile myelomonocytic leukemia (JMML) and moyamoya. We describe two affected siblings carrying a paternally inherited CBL variant (c.1210 T> C, p. Cys404Arg) who exhibited markedly divergent phenotypes, uncovering novel neuroinflammatory and systemic vascular fragility manifestations. The older sibling, a previously healthy 4-year-old girl, presented with acute, rapidly progressive acute disseminated encephalomyelitis (ADEM)-like neuroinflammatory disease post-febrile illness, accompanied by optic neuritis, and severe dystonia-parkinsonism. She had mild splenomegaly and thrombocytopenia. Brain MRI demonstrated extensive bilateral basal ganglia and diffuse white matter abnormalities, without evidence of moyamoya. Cerebrospinal fluid analysis showed pleocytosis and elevated protein, with extensive infectious and metabolic workups returning negative. Conversely, her 2-year-old sister presented with hematologic myeloproliferation and was diagnosed with JMML at 12 months. At 21 months, following an intercurrent viral infection, she presented with recurrent, bilateral arterial ischemic stroke and was diagnosed with severe, bilateral moyamoya. Vessel wall Imaging showed no enhancement. During hospitalization, she demonstrated profound systemic vascular fragility, manifested by a radial artery pseudoaneurysm post-puncture and a femoral artery pseudoaneurysm post-angiography, which required surgical repair. Bilateral encephaloduroarteriosynangiosis led to clinical stabilization. These cases extend the phenotypic spectrum of CBL-related disorders to include severe central nervous system immune dysregulation and systemic vascular fragility with recurrent peripheral arterial pseudoaneurysms. These findings demonstrate that CBL loss of function drives tissue-level proliferative and inflammatory remodeling, highlighting a novel intersection between dysregulated Ras/MAPK signaling, neuroinflammation, and structural vascular vulnerability.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2568-2574"},"PeriodicalIF":1.7,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306750","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 Genotypic and Phenotypic Spectrum of Li-Campeau Syndrome: A Homozygous Single-Exon Deletion in UBR7.","authors":"Tarik Duzenli, Damla Yıldız, Gulsum Kayhan, Hanife Saat, Pelin Özlem Şimşek-Kiper","doi":"10.1002/ajmg.a.70342","DOIUrl":"https://doi.org/10.1002/ajmg.a.70342","url":null,"abstract":"<p><p>Biallelic pathogenic variants in UBR7, encoding ubiquitin protein ligase E3 component n-recognin 7, cause Li-Campeau syndrome (LICAS; OMIM #619189), which is characterized by developmental delay/intellectual disability, epilepsy, hypothyroidism, ptosis, genital anomalies, and cardiac anomalies. LICAS is an ultrarare disorder, and to date, only nine patients from eight unrelated families have been reported with detailed clinical phenotypes. Here, we report an 18-year-old female patient with dysmorphic facial features, ptosis, congenital hypothyroidism, intellectual disability, stereotypic hand movements, attention-deficit/hyperactivity disorder, hepatosplenomegaly, and toenail hypoplasia. In contrast to previously reported patients, all of whom presented with global developmental delay, our patient achieved age-appropriate early motor and language milestones, representing the mildest early developmental course reported in LICAS to date. Exome sequencing revealed a homozygous deletion encompassing Exon 7 of UBR7, representing the first single-exon deletion reported in this gene. This report expands both the phenotypic and genotypic spectrum of LICAS and underscores the clinical utility of Next generation sequencing-based copy-number variant analysis in the diagnostic workup of rare diseases.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222991","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":"Neurobehavioral Profiles and Clinical Consequences of MYT1L-Related Neurodevelopmental Disorder: Insights From the Brain Gene Registry.","authors":"Jorge L Granadillo, Levi Kaster, Virginia Lanzotti, Daleep Grewal, Allyson Schreiber, Anna M Abbacchi, Christina A Gurnett, Kristen L Kroll, Dustin Baldridge, Heather C Hazlett, Leann Dawalt, John N Constantino, Aditi Gupta, Joseph D Dougherty","doi":"10.1002/ajmg.a.70321","DOIUrl":"https://doi.org/10.1002/ajmg.a.70321","url":null,"abstract":"<p><p>MYT1L-Related Neurodevelopmental Disorder (MYT1L-NDD) is a rare autosomal dominant syndrome characterized by intellectual disability, global developmental delay, autism, and obesity. Despite growing recognition, prospective and systematic clinical phenotyping remains limited. Here, we present an exploratory analysis of data from 25 individuals with MYT1L-NDD enrolled in the Brain Gene Registry (BGR), a national platform integrating genetic, neurobehavioral, and clinical data. Neurobehavioral assessments were conducted using the Rapid Neurobehavioral Assessment Protocol (RNAP), including virtual adaptations of the Shipley, Developmental Profile-4, ASEBA Child Behavior Checklist, and Vineland-3. Diagnostic and medication data were extracted from structured electronic health records (EHR). MYT1L-NDD participants were compared to the broader BGR cohort. MYT1L-NDD participants exhibited pronounced impairments in nonverbal cognition and adaptive functioning, particularly in motor tasks, communication, and daily living skills. Behavioral assessments revealed elevated rates of autism symptoms, ADHD symptoms, behavioral conduct problems, oppositional defiance, and anxiety. EHR diagnosis data were available for 10 MYT1L-NDD participants. It showed frequent diagnoses of developmental delays, speech and language disorders, intellectual disability, gastrointestinal problems, and obesity. Medication data on five participants indicated common prescription of alpha-2 adrenergic agonists and laxatives. This study provides the first prospective, multi-source characterization of MYT1L-NDD. Findings expand our understanding of MYT1L-NDD phenotypes in a quantitative and systematic manner and support the value of registry-based approaches for understanding rare neurodevelopmental disorders. Larger, longitudinal, age-stratified studies are needed to further define MYT1L-NDD natural history and inform clinical care.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219728","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":"Absent Septum Pellucidum Without Polymicrogyria or Seizures in TCP1-Related Neurodevelopmental Disorder.","authors":"David Biton, Dibyendu Dutta, Ria Garg","doi":"10.1002/ajmg.a.70335","DOIUrl":"https://doi.org/10.1002/ajmg.a.70335","url":null,"abstract":"<p><p>T-complex protein 1 (TCP1) encodes the TCP1α subunit, one of eight subunits of the chaperonin containing TCP1 ring complex (TRiC). Heterozygous TCP1 variants cause autosomal dominant neurodevelopmental disorder characterized by developmental delay or intellectual disability, seizures, pyramidal or cerebellar signs, and brain malformations, particularly polymicrogyria. However, the reported clinical spectrum remains limited. We report a 4-year-old girl with global developmental delay, speech and motor delay, behavioral dysregulation, microcephaly, hypotonia with core weakness, and a previously unreported heterozygous likely pathogenic TCP1 variant, c.1392delT (p.A465Qfs*3). This frameshift variant is located in exon 11, truncates the final 16.5% of the protein, is predicted to undergo nonsense-mediated decay, and is absent from gnomAD. Biological parental testing was unavailable, precluding determination of variant inheritance. Brain magnetic resonance imaging (MRI) demonstrated an absent septum pellucidum with mild bilateral frontal sulcation/gyration asymmetry without polymicrogyria; the optic nerves and pituitary were normal. No seizures were documented through age 4 years. Additional findings included bicuspid aortic valve with mild aortic insufficiency, asthma, severe eczema/atopy, and multiple food allergies. This case suggests that the molecular and neuroimaging spectrum of TCP1-related neurodevelopmental disorder may be broader than previously recognized; however, a causal association between TCP1 and absent septum pellucidum cannot be established from a single case. The relationship of the cardiac and atopic findings to TCP1 remains uncertain. Additional cases and functional studies are needed to clarify genotype-phenotype relationships.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223016","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}