American Journal of Medical Genetics Part A最新文献

{"title":"Presenting Clinical Information on Rare Chromosome 6 Disorders via a Parent-Centered Website: Parental and Professional Views.","authors":"Eleana Rraku, Aafke Engwerda, Tyler D Medina, Morris A Swertz, Lennart F Johansson, Conny M A van Ravenswaaij-Arts, Imke Christiaans","doi":"10.1002/ajmg.a.64038","DOIUrl":"https://doi.org/10.1002/ajmg.a.64038","url":null,"abstract":"<p><p>The scarcity of clinical information surrounding rare chromosome disorders poses challenges for parents and clinicians. To bridge this gap for chromosome 6 disorders, the Chromosome 6 Project collects detailed genotype and phenotype data, aiming to provide aberration-specific phenotype information to parents via an interactive website. With input from 32 parents and 21 professionals, including medical doctors, cytogeneticists, health psychologists, and communication specialists, we used a three-round Delphi method to determine the type and amount of health-related information to be presented on this website. A pre-Delphi questionnaire identified key factors for reporting clinical information online, forming the basis for 13 Delphi statements. Consensus was reached for 12 statements. Participants agreed that clinically relevant features should always be reported given their health impact, while parents also emphasized the importance of issues affecting the child's or family's well-being. Feature prevalence was supported as a guide for the order of reported features. To limit information overload, participants agreed on a reporting threshold for certain features. Finally, parents will be able to tailor the amount and type of information they view, with all details remaining accessible for future reference. While focused on chromosome 6 aberrations, these findings can inform the online information needs of families and professionals dealing with other rare genetic disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64038"},"PeriodicalIF":1.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623157","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":"Situs Inversus in an Infant With Hypomandibular Faciocranial Syndrome: Clinical Overlap With the Agnathia-Otocephaly Complex.","authors":"Jorge Román Corona-Rivera, Rocio Carolina Cortés-Pastrana, Natalia Navia-Espinoza, Alexandra María Claro-Marín, Ana Fátima Martínez-Torres, Christian Peña-Padilla, Lucina Bobadilla-Morales, Alfredo Corona-Rivera, Seung Woo Ryu, Go Hun Seo","doi":"10.1002/ajmg.a.64045","DOIUrl":"https://doi.org/10.1002/ajmg.a.64045","url":null,"abstract":"<p><p>There have been three previously reported cases of hypomandibular faciocranial syndrome (HFS), which is characterized by dysgnathia (an absent or hypoplastic mandible), a protruding lower face, microstomia, normally positioned ears, and craniosynostosis. The dysgnathia and oro-pharyngo-laryngeal abnormalities in HFS are virtually identical to those found in the agnathia-otocephaly complex (AOC), of which severe forms can include holoprosencephaly (HPE), synotia-melotia, and situs abnormalities, but not craniosynostosis. We report an infant with HFS who also presented with situs inversus totalis, which supports its pathogenic overlap with the AOC. The infant showed severe craniofacial asymmetry due to a complex craniosynostosis, microstomia, a hypoplastic tongue, and severe micrognathia, as well as situs inversus totalis. Exome sequencing did not identify any potentially causal variants. It has been noted that dysgnathia is most commonly associated with four distinctive anomalies: synotia-melotia, HPE, situs abnormalities, or craniosynostosis. Through a four-way Venn diagram, we identified eight predictable subsets of patients with dysgnathia that cover all possible phenotypic overlaps that may occur among patients with AOC. Using this approach, we identified that HFS should be conceptualized as a form of dysgnathia (or AOC) that is distinguishable by a distinctive presence of craniosynostosis and an absence of anomalies in the brain and ears, along with the situs abnormalities observed in this case.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64045"},"PeriodicalIF":1.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623159","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 Mosaic Hotspot PLCD1 Variant, Detectable in Blood-Derived DNA, Associated With Nevus Trichilemmocysticus.","authors":"Leanne de Kock, Macarena Nougues, Madeline Couse, Wendy Mears, Alison J Eaton, Kristin D Kernohan, Margarita Larralde, Kym M Boycott","doi":"10.1002/ajmg.a.64046","DOIUrl":"https://doi.org/10.1002/ajmg.a.64046","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64046"},"PeriodicalIF":1.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603488","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":"Unique DUP-TRP/INV-DUP Structure Detected by Long-Read Sequencing.","authors":"Rina Shimomura, Keiko Shimojima Yamamoto, Mutsuki Nakano, Takahiro Tayama, Tatsuo Mori, Eriko Nishi, Ken Inoue, Satoru Nagata, Nobuhiko Okamoto, Toshiyuki Yamamoto","doi":"10.1002/ajmg.a.64044","DOIUrl":"https://doi.org/10.1002/ajmg.a.64044","url":null,"abstract":"<p><p>Duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) is one of the mechanisms that causes genomic triplications. There are some characteristics of the DUP-TRP/INV-DUP; the appearance of a moving average of signal log2 ratio in genomic copy number analysis consisting of the highest center with lower steps on both sides; the chromosomal structure is composed of only two junctions; there are inverted repeats at the ends of the triplications and duplications on the same side and those connected in the opposite direction; and the size of the DUP-TRP/INV-DUP structure is generally less than the 1-Mb range. In this study, we analyzed two patients with DUP-TRP/INV-DUP involving PLP1 and MECP2. Whole-genome long-read sequencing was performed, and all breakpoint junctions were confirmed. Patient 1 showed a typical DUP-TRP/INV-DUP pattern involving PLP1, whereas Patient 2 showed a unique DUP-TRP/INV-DUP pattern in the MECP2 region, which involved additional chromosomal breakages at a 46-Mb far remote region of Xq22.3. Based on this finding, we suspected that chromosomal breakage at Xq22.3 was the initial damage. The detected two break ends were considered to be repaired by binding to the Xq28 region adjacent to the inverted repeat structure to form a triplication structure.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64044"},"PeriodicalIF":1.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603491","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":"Nanopore Sequencing Solves an Elusive Case of Sotos Syndrome.","authors":"Pasquale Di Letto, Alberto Budillon, Sarah Iffat Rahman, Francesca Del Vecchio Blanco, Mariateresa Zanobio, Margherita Scarpato, Margherita Russo, Maria Elena Onore, Giulio Piluso, Vincenzo Nigro, Gioacchino Scarano, Annalaura Torella","doi":"10.1002/ajmg.a.64039","DOIUrl":"https://doi.org/10.1002/ajmg.a.64039","url":null,"abstract":"<p><p>Sotos syndrome is a rare genetic disorder characterized by distinctive facial features, including a broad and prominent forehead, dolichocephaly, and learning disabilities ranging from mild to severe intellectual impairment. Affected individuals often show overgrowth in height and head circumference over two standard deviations. The syndrome is caused by haploinsufficiency of the NSD1 gene, with no evidence of genetic heterogeneity to date. Here we describe the unsolved case of a child of 4 years of age with a clinical diagnosis of Sotos syndrome. However, trio exome sequencing (ES) and exon chromosomal microarray (CMA) analysis excluded both small and large mutations in the NSD1 gene. As part of the Telethon Undiagnosed Programme, we used additional tools to investigate the possibility of new genes or elusive mutations that may have been missed by previous molecular diagnostic approaches. Therefore, we performed Nanopore long-read sequencing. This revealed a 447 bp insertion in exon 13 of the NSD1 gene. mRNA analysis confirmed in-frame skipping of exon 13 that encodes for two PHD domains. The genomic insertion shows 100% identity with an intronic region, although inverted, containing an AluSx1 element 2 kb upstream of the skipped exon, which may drive the event by masking the splice acceptor site of exon 13. Interestingly, this is the first case of Sotos syndrome linked to a pathogenic mechanism involving an insertion enclosing a transposable element generating a protein devoid of two PHDs, which are required for reading histone post-translational modifications.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64039"},"PeriodicalIF":1.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584333","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 the Molecular and Clinical Consequences of an Intragenic TRIP12 Duplication Using Genomic and RNA Analyses.","authors":"Haowei Du, Przemyslaw Szafranski, Amanda Gerard, Mahshid S Azamian, Weimin Bi, Mir Reza Bekheirnia, Paweł Stankiewicz","doi":"10.1002/ajmg.a.64036","DOIUrl":"https://doi.org/10.1002/ajmg.a.64036","url":null,"abstract":"<p><p>Clark-Baraitser syndrome is a rare neurodevelopmental disorder associated with the E3 ubiquitin-protein ligase gene TRIP12. Using chromosomal microarray analysis (CMA), long-range PCR, breakpoint sequencing, and RNA analyses, we studied a 6-year-old female presenting with developmental delay, aggressive behavior, attention-deficit hyperactivity disorder, and mild dysmorphic features. CMA revealed a de novo ~87 kb copy-number variant (CNV) duplication at 2q36.3, involving Exons 3-14 of TRIP12. Long-range PCR and Sanger sequencing showed a head-to-tail tandem duplication with breakpoints in Introns 2 and 14. RNA analysis identified a novel splicing junction between the coding Exon 14 and the stop codon of the noncoding portion of Exon 3, resulting in a premature translation termination. This suggests the neo-transcript undergoes nonsense-mediated decay and/or produces a truncated protein lacking the critical E6AP-type E3 ubiquitin-protein ligase domain. This case further highlights the challenges with the clinical interpretation of CNV gains and the usefulness of RNA sequencing in the clarification of the impacts of intragenic duplications.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64036"},"PeriodicalIF":1.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584334","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":"Functional Characterization of a Genetic Variant in the 5' UTR of APC 1B Promoter in a Familial Adenomatous Polyposis Family.","authors":"Brendon Young, Deborah W Neklason, Kathleen Clark, Bing-Jian Feng, Megan B Keener, Thérèse M Tuohy, Austin Wood, Wendy C McKinnon, Marc S Greenblatt, Sean V Tavtigian","doi":"10.1002/ajmg.a.63992","DOIUrl":"https://doi.org/10.1002/ajmg.a.63992","url":null,"abstract":"<p><p>Pathogenic germline variants in the APC gene result in familial adenomatous polyposis (FAP) which can escalate into colon cancer. Standard clinical testing failed to identify pathogenic variants in a 4-generation FAP family. We identified and assessed co-segregation of a 5' untranslated region (UTR) variant, NM_001127511.3 (APC) c.-40G>A (GRCh37 chr5:112043375) that creates a potential out-of-frame AUG start codon. The segregation odds of pathogenicity for the APC c.-40G>A variant are 159:1. Translation initiation confidence values for all possible AUGs in the 5' UTR created by a single nucleotide substitution were calculated using PreTIS online tool. The -40G>A variant scored the highest possible confidence value. To test -40G>A as an initiating methionine, we created reporter constructs consisting of the entire 5' UTR and first 81 bases of APC driving luciferase. When the -40G>A variant was present, luciferase activity was decreased to 14%-25% of the wild-type construct. When the premature start codon created by the -40G>A variant was in-frame with luciferase, we observed luciferase activity from this de novo false start site. Combined, our evidence supports classification of APC c.-40G>A to likely pathogenic, presumably through squelching of the canonical AUG start codon. More importantly, it underlines the feasibility and importance of clinical laboratories to screen noncoding regions.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63992"},"PeriodicalIF":1.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584332","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":"COL1A1 and COL1A2 Gene Variants Causing Osteogenesis Imperfecta in a Major Referral Center of India.","authors":"Agnes Selina, Madhavi Kandagaddala, Nihal Thomas, Thomas Paul, Aaron Chapla, Sumita Danda, Vrisha Madhuri","doi":"10.1002/ajmg.a.64023","DOIUrl":"https://doi.org/10.1002/ajmg.a.64023","url":null,"abstract":"<p><p>Heterozygous COL1A1 and COL1A2 gene variants are known to cause osteogenesis imperfecta (OI) in 90% of the patients in the Western and Japanese populations. Two previous Indian reports, a total of 49 patients, showed their proportion in the Indian population to be 44% and 71%. We studied a population of 210 children with a clinical diagnosis of OI and focused on the cohort of children with (likely) pathogenic COL1A1/COL1A2 variants. The prospective study describes the clinical, radiological, and genetic findings of 100 COL1A1/A2 variants. Phenotypic evaluation included the type of OI, fracture history, extraskeletal and skeletal features, pamidronate treatment, and its effect on bone density. Genotyping was assessed by clinical or targeted exome sequencing and validated by Sanger sequencing. One hundred patients, including affected siblings, out of 210 had COL1A1/A2 gene variants. No genetic cause was found in 25, and the remaining had causative variants in other OI-associated genes. In the group of 100 children with (likely) pathogenic COL1A1/A2 variants, the proportions of phenotypes 1, 3, and 4 were 24%, 44%, and 32%, respectively. Consanguinity was 10%, which was less when compared to the other OI-associated genes. The age of the first fracture was primarily at birth or before 6 months, particularly in severe types of OI such as Type III. Blue sclerae were observed in 84 patients, most commonly associated with OI Type I. Dentinogenesis imperfecta (DI) was present in 47 patients, typically seen in Types III and IV. Radiological features included Wormian bones in 58 patients, vertebral fractures in 46, and spine deformities in 16. Lower limb deformities were present in 90% of cases, with a higher prevalence in more severe forms of OI, while upper limb deformities were noted in 39%. Among the 22 patients receiving regular pamidronate therapy, there was a noticeable improvement in bone density, emphasizing the therapy's effectiveness, particularly in managing moderate to severe OI types. Genotypically, we report (likely) pathogenic 56 COL1A1 and 46 COL1A2 variants, including 21 novel variants. Of the 66 missense variants, 29 were in COL1A1 and 37 in COL1A2 genes. Of these, 60 were glycine substitutions (28 in COL1A1 and 32 in COL1A2) in the triple helix, the commonest being glycine to serine, associated with OI Type 3 in 28 individuals. The report highlights that 47.6% (100 out of 210 patients) of COL1A1 and COL1A2 gene variants were found in our cohort who underwent genetic analysis. This percentage is notably lower compared to other populations, where the percentage of identified COL1A1/2 variants has been reported to be higher.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64023"},"PeriodicalIF":1.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565768","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":"Unusual Presentation of Coronary Artery Fistula in Capillary Malformation Arteriovenous Malformation 2 Syndrome: A Case Report.","authors":"Tyson C Echols, Allison Britt, Seth E Vatsky, Sarah E Sheppard, Bryan A Pukenas, Alexandra J Borst","doi":"10.1002/ajmg.a.64041","DOIUrl":"10.1002/ajmg.a.64041","url":null,"abstract":"<p><p>Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a germline vascular dysplasia that is typically characterized by cutaneous capillary malformations and central nervous system arteriovenous malformations (AVM). We report an atypical presentation of CM-AVM2 featuring a giant coronary fistula. A 22-day-old male exhibited a cardiac murmur, leading to the discovery of a large fistula from the left circumflex coronary artery. The patient developed left eye exophthalmos due to a left-sided basilar to pontomesencephalic vein fistula. Genetic testing demonstrated a previously reported pathogenic ephrin type B-receptor 4 (EPHB4) variant c.175G>A, p.Glu59Lys, suggesting a diagnosis of CM-AVM2 syndrome. A variant of uncertain significance in GATA-binding factor 2 (GATA2) c.1289C>T, p.Ala430Val was also identified. Due to residual enlargement of the left coronary artery following fistula occlusion, the patient was initiated on warfarin and aspirin for dual anticoagulation and antiplatelet therapy. This uncommon presentation may warrant cardiac imaging for patients with CM-AVM syndrome presenting with a murmur or other cardiac symptoms. Further investigation is necessary to determine the incidence of cardiac involvement in patients with CM-AVM syndrome.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64041"},"PeriodicalIF":1.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565772","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 Genetic Variants Linked to Autism Identified in Diverse Populations","authors":"","doi":"10.1002/ajmg.a.63262","DOIUrl":"https://doi.org/10.1002/ajmg.a.63262","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 4","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564773","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}