American Journal of Medical Genetics Part A最新文献

{"title":"Lymphatic Abnormalities in Noonan Syndrome Extend Beyond Clinically Apparent Disease","authors":"Inger Norlyk Sheyanth,&nbsp;Benjamin Kelly,&nbsp;Sheyanth Mohanakumar,&nbsp;Steffen Ringgaard,&nbsp;Yoav Dori,&nbsp;Irene Kibæk Nielsen,&nbsp;Uffe Birk Jensen,&nbsp;Vibeke Elisabeth Hjortdal","doi":"10.1002/ajmg.a.70146","DOIUrl":"10.1002/ajmg.a.70146","url":null,"abstract":"<p>Lymphatic disease represents a well-described manifestation of Noonan syndrome (NS), yet the full phenotypic spectrum remains incompletely characterized, especially in asymptomatic individuals. We conducted a cross-sectional study including 10 individuals with NS (four with peripheral lymphedema and six without) and 10 age- and sex-matched cardiovascularly healthy controls. Central lymphatic anatomy was visualized using non-contrast T2-weighted MR-lymphangiography, and peripheral lymphatic morphology and function were assessed with near-infrared fluorescence (NIRF) imaging and strain gauge plethysmography (SGP). Variations in thoracic duct morphology were observed in 89% (8/9) of NS individuals compared to 20% (2/10) of controls. Thoracic lymphatic classifications (Biko/Dori scale) differed significantly in NS individuals, both with and without lymphedema, compared with healthy controls (<i>p</i> &lt; 0.05). Central lymphatic abnormalities were observed in five of nine NS individuals, including three without clinical signs of lymphatic disease. Abnormal peripheral conduction in collective vessels, characterized by retrograde or absent flow, was detected in all four NS individuals with lymphedema (<i>p</i> &lt; 0.05), while normal conduction was observed in asymptomatic NS individuals and controls. Findings from this study indicate that central lymphatic abnormalities may be present in NS regardless of symptom status, with abnormal peripheral conduction developing later in association with clinically manifest lymphedema. Central lymphatic abnormalities extend beyond clinically apparent disease and broaden the recognized phenotype, highlighting the value of lymphatic imaging for diagnosis and monitoring.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2211-2223"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrocardiographic and Skin Manifestations of Turner Syndrome: Association With Cardiovascular Disease","authors":"Sarah Elsaim,&nbsp;Brett Vernier,&nbsp;Van Thi Thanh Truong,&nbsp;Riya T. Patel,&nbsp;Matthew Brown,&nbsp;Martin Chacon Portillo,&nbsp;Megan Rogge,&nbsp;David Rodriguez-Buritica,&nbsp;Siddharth K. Prakash","doi":"10.1002/ajmg.a.70200","DOIUrl":"10.1002/ajmg.a.70200","url":null,"abstract":"<p>Congenital heart disease (CHD) and dermatologic conditions such as lymphedema and acquired melanocytic nevi (AMN) are common in Turner Syndrome (TS). We hypothesized that abnormalities of cranial neural crest cell derivatives drive the skin and heart manifestations of TS. We conducted joint cardiac and skin examinations of volunteers at a 2023 national TS conference. Electrocardiographic abnormalities were classified according to the Minnesota Codes. Aortic diameters and cardiac anatomy were assessed using a standardized echocardiographic protocol. The primary outcome was the association between ECG abnormalities and thoracic aortic aneurysms (TAA) or CHD. The secondary outcome was the association between AMN counts and CHD, TAA, or the corrected QT interval (QTc). Among 118 participants (median age 33 years; CHD 39%; TAA ~25%), 35% had major ECG abnormalities, most commonly T-wave inversions and ST depressions; QTc prolongation occurred in 7%. Major ECG abnormalities were associated with larger aortic diameter and were more frequent in CHD, with a trend toward increased TAA (OR 2.8). Notably, 17% without known CHD had ECG abnormalities, and &gt; 25% of these had previously unrecognized TAA. Only 45,X karyotype independently predicted ECG abnormalities. AMN burden was markedly elevated and increased stepwise with combined CHD + TAA (adjusted OR per level 13.1) but was not associated with QTc. ECG abnormalities and AMN burden track with cardiovascular disease severity in TS and may identify individuals with unrecognized aortopathy. These preliminary findings support integrated multimodal screening for CHD in TS, pending validation in larger cohorts.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2234-2240"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Genetic and Clinical Spectrum of GZF1-Related Phenotype: A Specific Ocular and Skeletal Disorder Distinguishable From Larsen Syndrome","authors":"Emiy Yokoyama-Rebollar,&nbsp;Camilo E. Villarroel,&nbsp;Tania Barragán-Arévalo,&nbsp;Oscar Francisco Chacón-Camacho,&nbsp;Diana Cristina Orozco-Ávila,&nbsp;Paula Leal-Anaya,&nbsp;Victoria del Castillo-Ruiz,&nbsp;Juan Carlos Zenteno","doi":"10.1002/ajmg.a.70207","DOIUrl":"10.1002/ajmg.a.70207","url":null,"abstract":"<div>\u0000 \u0000 <p>GZF1-related phenotype (GZF1RP) has been referred to by different names, including autosomal recessive Larsen syndrome (LRS) and “joint laxity, short stature, and myopia”. Only ten patients from five families have been reported, all of whom carry biallelic variants of <i>GZF1</i>. They share short stature and joint dislocation with LRS; however, they present with severe ocular manifestations, suggesting that GZF1RP may be specific. In this study, we described three new patients with severe ophthalmologic phenotypes, including congenital glaucoma and abnormal iris morphology. We identified the <i>GZF1</i>: c.1440del (p.His481IlefsTer26) variant in homozygosity in two affected sisters and compound heterozygosity in the third patient: the same c.1440del plus c.1451_1452del (p.Cys484fs). In addition to expanding the molecular spectrum, we identified new radiological findings, such as cervical segmentation defects, carpal shortening, and lower lumbar sacralization, as well as some clinical findings uncommon in previous cases, such as umbilical hernia and congenital heart disease. We also searched for LRS case series with pathogenic variants in <i>FLNB</i> to identify differences between the two entities. The comparison allows us to define a recognizable GZF1RP that includes severe ocular defects, short stature, facial dysmorphism, joint hypermobility/dislocations, scoliosis, thoracic deformity, progressive hearing loss, umbilical hernia, and hypodontia.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2309-2319"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986246","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":"FGF12-Related Early-Onset Epileptic Encephalopathies: Therapeutic Response to Sodium Channel Blockers","authors":"Fatimah Aldurayhim,&nbsp;Sulman Basit,&nbsp;Shahid Bashir,&nbsp;Yousef Hussain Housawi,&nbsp;Ali Mir","doi":"10.1002/ajmg.a.70182","DOIUrl":"10.1002/ajmg.a.70182","url":null,"abstract":"<div>\u0000 \u0000 <p>Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal ion channels or synaptic proteins. The fibroblast growth-factor 12 (<i>FGF12</i>) encodes a binding protein for voltage-gated sodium channels. Variants in <i>FGF12</i> have recently been associated with autosomal dominant DEEs characterized by early-onset epilepsy and neurodevelopmental impairment. We report three patients with a duplication involving exons 1–4 of <i>FGF12</i> on chromosome 3q28–q29 and systematically review 24 previously published cases of <i>FGF12</i>-related DEE. Clinical features, electroencephalographic findings, neuroimaging data, and responses to anti-seizure medications (ASMs) were analyzed across a total cohort of 27 patients. Eighteen patients carried <i>FGF12</i> missense variants, including the recurrent pathogenic p.Arg114His variant (<i>n</i> = 14), p.Gly112Ser (<i>n</i> = 2), p.Glu87Lys (<i>n</i> = 1), and one exon 4 missense variant (chr3:g.192335434C&gt;T). Nine patients had copy number duplications involving <i>FGF12</i>. Seizure onset ranged from 1 day to 4 years of age, with 54.1% presenting in the neonatal period. Tonic seizures were the most common seizure type, and 79.1% of patients exhibited moderate to severe intellectual disability. Brain MRI showed mild cerebral and/or cerebellar atrophy in 41.6% of cases. Across reported cases, variable responsiveness to ASMs was observed, with sodium channel blockers including carbamazepine and phenytoin frequently associated with seizure reduction. This study expands the clinical and genetic spectrum of <i>FGF12</i>-related DEE and highlights considerable phenotypic variability across variant types. While treatment responses were heterogeneous, sodium channel blockers were commonly associated with clinical improvement. These findings support cautious consideration of sodium channel targeting therapies in <i>FGF12</i>-DEE and underscore the need for systematic studies to better define genotype treatment relationships.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2199-2210"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759441","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":"Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings","authors":"Yiyoung Kwon,&nbsp;Sukyung Kim,&nbsp;Yoon Zi Kim,&nbsp;Tae Jong Jeong,&nbsp;Minji Im,&nbsp;Sang Yun Ha,&nbsp;Tae Yeon Jeon,&nbsp;Yon Ho Choe,&nbsp;Sung Yoon Cho,&nbsp;Mi Jin Kim,&nbsp;Gyu-Seong Choi,&nbsp;Sanghoon Lee","doi":"10.1002/ajmg.a.70201","DOIUrl":"10.1002/ajmg.a.70201","url":null,"abstract":"<div>\u0000 \u0000 <p>Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in <i>SMAD4</i> and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed <i>SMAD4</i> p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated <i>SMAD4</i>–TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2250-2259"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939435","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":"Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics","authors":"Teresa Zhao,&nbsp;Andrew P. Fennell,&nbsp;Tanavi Sharma,&nbsp;Katrina M. Bell,&nbsp;Monique Dunstan,&nbsp;Sebastian Lunke,&nbsp;Meagan J. McGrath,&nbsp;Catriona McLean,&nbsp;Undiagnosed Diseases Network (UDN-Aus),&nbsp;David R. Thorburn,&nbsp;David A. Stroud,&nbsp;John Christodoulou","doi":"10.1002/ajmg.a.70191","DOIUrl":"10.1002/ajmg.a.70191","url":null,"abstract":"<p>TECPR2 is a key regulator of autophagy, encoded by the <i>TECPR2</i> gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the <i>TECPR2</i> gene, NM_014844.4: c.480G&gt;A; p.(Gln160=) and c.2846C&gt;A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were <i>in trans</i>. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2338-2344"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms","authors":"Victoria Mok Siu,&nbsp;Rosan Kenana,&nbsp;Rana Chakrabarti,&nbsp;Sarah D. P. Wilhelm,&nbsp;Joseph Andrews,&nbsp;Susan J. Leat,&nbsp;Christina Parker,&nbsp;Michael Miller,&nbsp;Leslie A. Nangle,&nbsp;Wendy McCaul,&nbsp;Ashfia Chowdhury,&nbsp;Natalie Hutchings,&nbsp;Ryan A. Adams,&nbsp;Lauren Guy,&nbsp;Mandy Rhody,&nbsp;Verena Juncal,&nbsp;Marisa I. Mendes,&nbsp;Desiree E. C. Smith,&nbsp;Gajja S. Salomons,&nbsp;Angelica A. Moresco,&nbsp;Daphne L. McCulloch,&nbsp;D. Holmes Morton,&nbsp;Ilka U. Heinemann,&nbsp;C. Anthony Rupar","doi":"10.1002/ajmg.a.70203","DOIUrl":"10.1002/ajmg.a.70203","url":null,"abstract":"<p>Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2289-2308"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Ancestry and Carrier Variant Frequency Enrichment in a Colombian Andean Population: Insights From the Eje Cafetero","authors":"Gloria Liliana Porras-Hurtado,&nbsp;Alejandro Mejía-García,&nbsp;Stiven Ernesto Sinisterra-Diaz,&nbsp;Camilo Andres Velandia-Piedrahita,&nbsp;José Geles,&nbsp;Harry Pachajoa,&nbsp;Sandra Bello,&nbsp;Jubby Marcela Gálvez","doi":"10.1002/ajmg.a.70185","DOIUrl":"10.1002/ajmg.a.70185","url":null,"abstract":"<div>\u0000 \u0000 <p>Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal recessive disorders, particularly in semi-isolated Andean populations such as the Eje Cafetero. However, exome-based reference data from this region remain scarce, limiting ancestry-aware variant interpretation and carrier screening strategies. We aimed to characterize the ancestry proportions of this population using exome data, and to estimate the carrier frequency and distribution of pathogenic and likely pathogenic (P/LP) variants in clinically relevant recessive genes. We conducted a cross-sectional study with whole-exome sequencing (WES) in 316 unrelated individuals from the Colombian Eje Cafetero. P/LP variants were evaluated in 454 genes associated with autosomal recessive disorders. The global ancestry proportions were estimated using a validated panel of 250 exome-compatible ancestry-informative markers. Carrier frequencies were compared against Non-Finnish Europeans (NFE) and Admixed Americans (AMX) from gnomAD v4. The cohort showed predominant European ancestry (mean 51%), followed by Native American (36%) and African (13%) components. We identified 151 carriers of 89 distinct pathogenic variants across autosomal recessive genes. The most frequent variants were <i>SERPINA1</i> c.863A&gt;T (5.5%), <i>CFTR</i> c.1210–11T&gt;G (3.5%), and <i>PYGM</i> c.1094C&gt;T (1.5%). Also, recurrent variants were significantly enriched compared with both NFE and AMX populations, supporting regional founder effects. This study represents one of the most comprehensive exome-based genetic characterizations of the Colombian Eje Cafetero, revealing ancestry-specific enrichment of clinically relevant autosomal recessive variants driven by founder effects.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2224-2233"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809226","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":"Clinical Outcomes and Patient Experiences With Celiprolol Therapy in Vascular Ehlers–Danlos Syndrome: The First Non-European Cohort","authors":"Megumi Furuhata-Yoshimura,&nbsp;Tomomi Yamaguchi,&nbsp;Tomoki Kosho","doi":"10.1002/ajmg.a.70178","DOIUrl":"10.1002/ajmg.a.70178","url":null,"abstract":"<p>Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder caused by heterozygous pathogenic variants in <i>COL3A1</i>. European studies have shown that celiprolol may reduce the risk of life-threatening vascular events, but outcomes in non-European populations and the therapy's psychological impact remain unclear. We conducted a retrospective cohort study of individuals aged ≥ 20 years with genetically confirmed vEDS in a single referral center in Japan between 2000 and 2024. Clinical, molecular, and treatment data were obtained from medical records, and semi-structured interviews were conducted with a subset of participants to assess patient experiences. Twenty-six patients were included. The mean age at celiprolol initiation was 36.9 years, with a mean follow-up of 96.6 months. All patients received celiprolol, and 61.5% reached the target dose (400 mg/day). One patient died of hepatic artery rupture; vascular events occurred in 11, while 14 remained event-free. No significant associations were observed between vascular event occurrence and genotype or celiprolol dose. Interviews with 11 patients revealed that celiprolol use provided emotional reassurance and promoted a more proactive approach to disease management. Celiprolol therapy may reduce fatal vascular events in vEDS and have a positive psychological impact, though nonfatal vascular complications remain frequent.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2241-2249"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Homozygous p.(Arg215Ter) Variant in XRCC2 Is Associated With Atypical Fanconi Anemia Without Major Hematological Abnormalities in Childhood","authors":"Sabina Cenciarelli,&nbsp;Giulia Bruna Marchetti,&nbsp;Maria Iascone,&nbsp;Maria Grazia Patricelli,&nbsp;Sara Giangiobbe,&nbsp;Gabriella Cinzia Pozzobon,&nbsp;Miriam Nella Savini,&nbsp;Fabio Giglio,&nbsp;Alessandro Aiuti,&nbsp;Paola Carrera,&nbsp;Francesca Ferrua,&nbsp;Angela Peron","doi":"10.1002/ajmg.a.70171","DOIUrl":"10.1002/ajmg.a.70171","url":null,"abstract":"<p>Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the <i>XRCC2</i> gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far, and no long-term follow-up is available. Here we present two young related adults born to consanguineous parents, in whom we identified the homozygous p.(Arg215Ter) variant in <i>XRCC2</i>. Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. Unlike in FA, DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected until the age of 19 and 20 years, respectively. Our report suggests that the homozygous p.(Arg215Ter) variant in <i>XRRC2</i> causes a distinctive FA-like disorder, characterized by the typical physical characteristics seen in FA, but a lack of major hematological manifestations in childhood, and the presence of a more pronounced neurodevelopmental phenotype than that seen in FA.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2331-2337"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}