American Journal of Medical Genetics Part A最新文献

{"title":"Report From the International Conference on Incontinentia Pigmenti: Translating Discovery to Therapy.","authors":"Reid Wilson, Nicole Somani, Nancy Arias, Audina Berrocal, Connie Chen, Xi Chen, Emily Cole, Phillip Ehrich, Teresa Christina Faupel, Philip Ferrone, Tim Fete, Mary Fete, Francesca Fusco, Morton Goldberg, Dorothy Katherine Grange, Ian Han, Mary Elizabeth Hartnett, Aliyah King, Jacques Monnet, Eric Nudleman, Shirley Parraga, Jeremie Rosain, Maddison Salois, Markus Schwaninger, Ezia Spinosa, Saravanan Thangarajan, Eric Van Otterloo, Timothy Wright, Sandra Montezuma, John Peter Campbell","doi":"10.1002/ajmg.a.70195","DOIUrl":"10.1002/ajmg.a.70195","url":null,"abstract":"<p><p>Incontinentia pigmenti (IP) is a rare, X-linked dominant condition characterized by a perinatal rash as well as abnormalities of the central nervous system (CNS), eyes, hair, nails, and teeth. The CNS and ophthalmic manifestations are potentially severe and may lead to neurologic impairment and vision loss. Due to the rarity of IP, there remains a limited understanding of its physiology, and the guidelines for screening, clinical staging, and management of complications remain controversial. To address these gaps, a multidisciplinary, international conference on IP was held in Charlotte, North Carolina, from February 21 to 23, 2025. The meeting was hosted by the National Foundation for Ectodermal Dysplasias and the Oregon Health Sciences University. This report summarizes the discussion and recommendations from the conference, including guidance for screening of ophthalmic complications, as well as next steps for pursuing therapeutic interventions.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2384-2392"},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866246","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":"Defining Features of Gabriele-de Vries Syndrome in Adults: A Case Report and Literature Review.","authors":"Ethan W Hollingsworth, Changrui Xiao","doi":"10.1002/ajmg.a.70179","DOIUrl":"10.1002/ajmg.a.70179","url":null,"abstract":"<p><p>Gabriele-de Vries syndrome (GADEVS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the YY1 gene. Like most rare genetic syndromes, the adult manifestations of GADEVS remain poorly defined. Here, we describe the oldest patient reported to date with GADEVS-a 63-year-old woman with a c.1177_1179del YY1 variant, presenting with mild intellectual disability, bilateral cataracts, and early-onset coronary artery disease. We further review the shared and unique features across all adult patients with GADEVS in the literature. Together, this case report and review aim to broaden the phenotypic spectrum of patients with GADEVS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2396-2404"},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832277","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":"Revertant Mosaicism Obscures Long-Awaited Molecular Confirmation of Diamond-Blackfan Anemia.","authors":"Nicholas A Borja, Mustafa Tekin","doi":"10.1002/ajmg.a.70209","DOIUrl":"10.1002/ajmg.a.70209","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2381-2383"},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004330","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":"Computer-Aided Facial Analysis and Non-Coding Variants Detectable by Exome Sequencing Increase Its Diagnostic Yield: Results From the DECIPHERD Study.","authors":"Daniela Böhme, Víctor Faundes, María Cecilia Poli, Boris Rebolledo-Jaramillo, Catalina Lagos, Joan Orellana, Gabriela Moreno, Luz María Martín, Gonzalo Encina, María Jesús Zavala, Trinidad Hasbún, Camila Astudillo, Carolina Cares, Mariana Aracena, Catalina Samsó, Fernanda Espinosa, Marcela Díaz, Evelyn Silva, Gabriela M Repetto","doi":"10.1002/ajmg.a.70320","DOIUrl":"https://doi.org/10.1002/ajmg.a.70320","url":null,"abstract":"<p><p>While exome sequencing (ES) reanalysis is recommended for patients undiagnosed after initial analysis, the combination of computer-aided facial phenotyping with targeted examination of non-coding variants remains underexplored. We aimed to identify the molecular etiology in undiagnosed cases from the DECIPHERD study (n = 167) through trio ES reanalysis guided by a computer-aided facial analysis. We selected 47 patients who remained undiagnosed after initial testing and whose facial photographs were available. Genes were prioritized based on facial analysis using Face2Gene. Subsequently, we scrutinized these prioritized genes for non-coding variants detectable by ES. This strategy increased the diagnostic yield by 0.6% (1/167). We confirmed the diagnosis of Kabuki syndrome in one patient harboring a likely pathogenic variant in KMT2D. Additionally, we identified compound heterozygous variants of uncertain significance in CEP290 in a second patient, suggestive of Meckel syndrome. As these variants remain functionally unconfirmed, this second case is reported as a candidate molecular diagnosis rather than an established one. This approach may represent a low-cost first step to unveil additional diagnoses without recourse to more expensive genomic testing.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102783","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 TUBB2A Variant Causing Ataxia With Preserved Ambulation Into Adulthood.","authors":"João Cláudio da Costa Urbano, Sérgio Roberto Pereira da Silva Júnior, Matheus Augusto Araújo Castro, Paulo Ribeiro Nóbrega, José Tarcísio Medeiros de Vasconcelos, Leandro Tavares Lucato, Fernando Kok, Fernando Freua","doi":"10.1002/ajmg.a.70183","DOIUrl":"10.1002/ajmg.a.70183","url":null,"abstract":"<p><p>Pathogenic TUBB2A variants are known to cause a rare form of autosomal dominant tubulinopathy. Our aim is to expand the phenotypic spectrum of TUBB2A by documenting a milder phenotype caused by a previously unreported pathogenic variant. We report a newly diagnosed case of TUBB2A tubulinopathy with novel clinical findings of ataxia with preserved ambulation into adulthood, in addition to the already characteristic findings of global developmental delay in childhood, cortical malformations, and epilepsy. Informed consent was obtained for this publication. A 40 year-old man presented to the clinic with a history of global developmental delay, intellectual disability, myoclonic epilepsy, cerebellar ataxia and cortical malformations. We performed exome sequencing, which revealed a monoallelic variant in TUBB2A NM_001069.3: c.620 T>C;p.(Leu207Pro) classified as likely pathogenic. TUBB2A variants may cause slowly progressive ataxia along with global developmental delay and epilepsy. This case widens the phenotypical spectrum and provides a new clinical clue for physicians.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2393-2395"},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759684","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":"First National Expanded Genomic Newborn Screening Program in Qatar; A Pilot Study, Doha-Heidelberg Collaboration.","authors":"Reem Alsulaiman, Sarah Okashah, Radja Messai Badji, Fatemeh Abbaszadeh, Yaser Alsarraj, Rehab Ali Abdulrahman, Noora Shahbeck, Thalib Moideen, Reema El Hassan, Fatima Al-Hamaydeh, Einas Alkuwari, Said Ismail, Hilal Al- Rifai, Ghassan Abdoh, Christian P Schaaf, Georg Hoffmann, Saad Al-Kaabi, Wadha Al-Muftah, Tawfeg Ben-Omran","doi":"10.1002/ajmg.a.70186","DOIUrl":"10.1002/ajmg.a.70186","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"2374-2380"},"PeriodicalIF":1.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947422","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":"Correction to \"De Novo 2.2 Mb 19q13.42-q13.43 Microdeletion Encompassing U2AF2: Support for a Haploinsufficiency Model\".","authors":"","doi":"10.1002/ajmg.a.70311","DOIUrl":"https://doi.org/10.1002/ajmg.a.70311","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073505","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":"Differential Diagnosis of Mucopolysaccharidoses Types I, II, III, IVA, and VI Through Analysis of Leukocytic Inclusions.","authors":"Márcio A W Melo, Marcelo S Kertenetzky, Cristina M Silveira, Maíra M Ribeiro, Paula F Medeiros, Gabriela S Arcanjo","doi":"10.1002/ajmg.a.70316","DOIUrl":"https://doi.org/10.1002/ajmg.a.70316","url":null,"abstract":"<p><p>Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs), which can lead to cytoplasmic alterations in leukocytes. The objective of this study was to characterize leukocyte inclusions in patients with different types of MPS and assess their diagnostic relevance. A total of 69 Brazilian patients diagnosed with five MPS types were evaluated through cytological analysis of peripheral blood smears. Distinct leukocyte inclusion patterns were observed in four subtypes. In MPS Type II, small violet cytoplasmic inclusions were present in lymphocytes. In MPS Type III, larger violet inclusions were identified in lymphocytes. Patients with MPS Type IVA showed large, sparse granulations in neutrophils, while those with MPS Type VI exhibited coarse inclusions in all leukocytes, characteristic of the Alder-Reilly anomaly. No leukocyte inclusions were found in MPS Type I. These observations demonstrate that leukocyte inclusions vary according to MPS subtype and may represent a useful auxiliary cytological finding. Their identification may support diagnostic suspicion and contribute to the differential diagnosis of MPS II, III, IVA, and VI, complementing enzymatic and biochemical testing.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068825","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":"Guillouet-Gordon Syndrome With Severe Microtia in an Infant With a Homozygous Variant in MED16.","authors":"Sarah E Seese, Linda M Reis, Allison Genchanok, Hannah Brodner, Jessica A Smith, Steven R Leuthner, Michael Muriello, Elena V Semina","doi":"10.1002/ajmg.a.70315","DOIUrl":"https://doi.org/10.1002/ajmg.a.70315","url":null,"abstract":"<p><p>Bi-allelic MED16 variants underlie the recently described MEDopathy termed Guillouet-Gordon syndrome (GGNS, MIM #621220), characterized by neurodevelopmental and structural anomalies. To date, 27 individuals with GGNS have been reported, collectively harboring 28 distinct compound heterozygous or homozygous MED16 variants. Here we present a male infant, born to unrelated parents, presenting with multiple congenital anomalies overlapping with the established GGNS phenotypic spectrum. Specifically, the clinical presentation included structural brain defects and neurodevelopmental deficits alongside significant craniofacial (microretrognathia, cleft palate, auricular/nasal features), cardiac (double outlet right ventricle), renal (horseshoe kidney), ocular (colobomatous microphthalmia), and hand/foot (syndactyly, nail hypoplasia) anomalies, fetal growth restriction, neonatal respiratory distress, and premature death in the first month of life. Notably, while different outer ear anomalies have been previously described in GGNS, the severe bilateral microtia and post-auricular skin tag identified in this individual extend the known clinical spectrum of the syndrome. Trio exome analysis identified a novel likely pathogenic homozygous missense variant in MED16, c.1573C>T p.(Arg525Trp). The p.(Arg525Trp) variant shows a relatively high population frequency (0.00025 in gnomAD v4.1), with no homozygotes identified to date. The elevated carrier frequency of this and other MED16 variants suggests a potential role in additional individuals with unexplained multiple congenital anomalies.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056838","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 Systematic Review of Positron Emission Tomography (PET) in X-Linked Adrenoleukodystrophy: Beyond Structural MRI.","authors":"Yutaka Furuta, Hong Li, Stephanie R Keller, John A Phillips, Rory J Tinker, Eishi Asano, Csaba Juhász","doi":"10.1002/ajmg.a.70313","DOIUrl":"https://doi.org/10.1002/ajmg.a.70313","url":null,"abstract":"<p><p>X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very long-chain fatty acids and risk of progressive neuroinflammatory demyelination in the cerebral form of ALD. Brain MRI is the current standard neuroimaging modality for diagnosis and monitoring of central nervous system involvement. However, MRI primarily detects structural abnormalities and may not fully reflect functional impairment, neuroinflammatory activity, or early cerebral involvement. Positron emission tomography (PET) may provide complementary information beyond conventional MRI. Therefore, we aimed to review the current literature on PET imaging in X-ALD. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 26, 2026. Studies evaluating brain PET imaging in individuals with X-ALD were included. Data on study design, phenotype, ABCD1 genotype, brain MRI findings, PET tracers, analytic methods, and key findings were extracted. A total of 48 records were screened, resulting in the inclusion of 10 case reports and one case series comprising 12 patients. PET tracers included ¹⁸F-fluorodeoxyglucose (FDG) (N = 19 patients), ¹¹C-(R)-PK11195 (N = 1), and L-[methyl-¹¹C]methionine (N = 1). One additional patient underwent PET assessment of cerebral blood flow and oxygen metabolism using unspecified tracers. In FDG-PET studies, cortical hypermetabolism was reported in 12/19 individuals, whereas cortical hypometabolism was observed in 18/19 individuals, with findings in one case being either not specified or inconclusive. FDG-PET demonstrated cortical glucose hypometabolism overlying the affected white matter (WM) in 6/18 individuals with T2 and/or FLAIR-hyperintense WM lesions on MRI. FDG-PET demonstrated cortical glucose hypometabolism in 12/18 individuals without WM lesions on MRI. The FDG-PET findings were reported to correlate with clinical symptoms. Neuroinflammation-targeted ¹¹C-(R)-PK11195 PET demonstrated increased tracer binding in active WM lesions. Similarly, protein synthesis-targeted L-[methyl-¹¹C]methionine PET demonstrated increased tracer uptake in active WM lesions. PET may detect functional and neuroinflammatory abnormalities beyond those identified by structural MRI in individuals with X-ALD, suggesting a potential role in evaluating the extent and severity of brain involvement. However, the available evidence is limited by small sample sizes, underrepresentation of pediatric and presymptomatic cases, heterogeneous PET tracers and analytic methodologies, and a lack of longitudinal data. Further multimodal and longitudinal studies are needed to establish the clinical utility of PET as a surveillance tool in X-ALD.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056809","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}