Genetics in Medicine最新文献

{"title":"Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.","authors":"Daniel G Calame, Jovi Huixin Wong, Puravi Panda, Dat Tuan Nguyen, Nancy C P Leong, Riccardo Sangermano, Sohil G Patankar, Mohamed S Abdel-Hamid, Lama AlAbdi, Sylvia Safwat, Kyle P Flannery, Zain Dardas, Jawid M Fatih, Chaya Murali, Varun Kannan, Timothy E Lotze, Isabella Herman, Farah Ammouri, Brianna Rezich, Stephanie Efthymiou, Shahryar Alavi, David Murphy, Zahra Firoozfar, Mahya Ebrahimi Nasab, Amir Bahreini, Majid Ghasemi, Nourelhoda A Haridy, Hamid Reza Goldouzi, Fatemeh Eghbal, Ehsan Ghayoor Karimiani, Amber Begtrup, Houda Elloumi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Haowei Du, Shalini N Jhangiani, Zeynep Coban-Akdemir, Dana Marafi, Lance Rodan, Sedat Isikay, Jill A Rosenfeld, Subhadra Ramanathan, Michael Staton, Kerby C Oberg, Robin D Clark, Catharina Wenman, Sam Loughlin, Ramy Saad, Tazeen Ashraf, Alison Male, Shereen Tadros, Reza Boostani, Ghada M H Abdel-Salam, Maha Zaki, Ali Mardi, Farzad Hashemi-Gorji, Ebtesam Abdalla, M Chiara Manzini, Davut Pehlivan, Jennifer E Posey, Richard A Gibbs, Henry Houlden, Fowzan S Alkuraya, Kinga Bujakowska, Reza Maroofian, James R Lupski, Long N Nguyen","doi":"10.1016/j.gim.2024.101273","DOIUrl":"10.1016/j.gim.2024.101273","url":null,"abstract":"<p><strong>Purpose: </strong>FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1^-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.</p><p><strong>Methods: </strong>We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.</p><p><strong>Results: </strong>We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with Flvcr1^-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.</p><p><strong>Conclusion: </strong>These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilization of a SNP microarray to detect uniparental disomy: Implications and outcomes","authors":"","doi":"10.1016/j.gim.2024.101275","DOIUrl":"10.1016/j.gim.2024.101275","url":null,"abstract":"<div><h3>Purpose</h3><div>To examine the utility of single-nucleotide polymorphisms (SNP) microarray analysis to detect uniparental disomy (UPD) by utilizing trios and duos (for which only 1 parent is available).</div></div><div><h3>Methods</h3><div>We established Mendelian Inheritance Error (MIE) values associated with either UPD or biparental inheritance in a cohort of 124 patients. In duos, the percentage of proband heterozygous (AB) SNPs contributed from the parent submitted was also used to detect UPD.</div></div><div><h3>Results</h3><div>Examination of 25 trios revealed UPD with a MIE = 0.02 +/− 0.02 and a range of 0.01 to 0.23 for the contributing parent and a MIE = 8.76 +/− 1.68 with a range of 5.96 to 11.14 for the noncontributing parent. Detailed examination of 13 duos (involving 16 chromosomes) showed an AB% = 52.0% +/− 4.85% consistent with biparental origin of the chromosome of interest. In 6 duos (6 chromosomes), the AB% = 97.2% +/− 2.6% and a range of 92.9% to 99.4% were consistent with UPD.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate utility of a SNP microarray to detect UPD. Distinct MIE ranges were observed that defined UPD or biparental inheritance. In duos, the AB% calculation effectively detected UPD. The diagnostic yield for UPD testing is significantly decreased when large regions of homozygosity are not detected by routine microarray analysis, which has implications for UPD test ordering practices.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.","authors":"Rocio Rius, Alison G Compton, Naomi L Baker, Shanti Balasubramaniam, Stephanie Best, Kaustuv Bhattacharya, Kirsten Boggs, Tiffany Boughtwood, Jeffrey Braithwaite, Drago Bratkovic, Alessandra Bray, Marie-Jo Brion, Jo Burke, Sarah Casauria, Belinda Chong, David Coman, Shannon Cowie, Mark Cowley, Michelle G de Silva, Martin B Delatycki, Samantha Edwards, Carolyn Ellaway, Michael C Fahey, Keri Finlay, Janice Fletcher, Leah E Frajman, Ann E Frazier, Velimir Gayevskiy, Roula Ghaoui, Himanshu Goel, Ilias Goranitis, Matilda Haas, Daniella H Hock, Denise Howting, Matilda R Jackson, Maina P Kava, Madonna Kemp, Sarah King-Smith, Nicole J Lake, Phillipa J Lamont, Joy Lee, Janet C Long, Mandi MacShane, Evanthia O Madelli, Ellenore M Martin, Justine E Marum, Tessa Mattiske, Jim McGill, Alejandro Metke, Sean Murray, Julie Panetta, Liza K Phillips, Michael C J Quinn, Michael T Ryan, Sarah Schenscher, Cas Simons, Nicholas Smith, David A Stroud, Michel C Tchan, Melanie Tom, Mathew Wallis, Tyson L Ware, AnneMarie E Welch, Christine Wools, You Wu, John Christodoulou, David R Thorburn","doi":"10.1016/j.gim.2024.101271","DOIUrl":"10.1016/j.gim.2024.101271","url":null,"abstract":"<p><strong>Purpose: </strong>Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.</p><p><strong>Methods: </strong>A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.</p><p><strong>Results: </strong>Diagnostic yield was 55% (n = 77) with variants in nuclear (n = 37) and mtDNA (n = 18) MD genes, as well as phenocopy genes (n = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.</p><p><strong>Conclusion: </strong>Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Bayesian point-based system on the variant classification of hereditary cancer predisposition genes","authors":"","doi":"10.1016/j.gim.2024.101276","DOIUrl":"10.1016/j.gim.2024.101276","url":null,"abstract":"<div><h3>Purpose</h3><div>To assess the differences in variant classifications using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines and the Bayesian point-based classification system (here referred to as the point system) in 115 hereditary cancer predisposition genes and explore variant sub-tiering by the point system.</div></div><div><h3>Methods</h3><div>Germline variant classifications for 721 pediatric patients from an in-house panel were retrospectively evaluated using the 2 scoring systems.</div></div><div><h3>Results</h3><div>A total of 2376 unique variants were identified, with ∼23.5% exhibiting discordant classifications. Unique variants classified by the point system demonstrated a lower rate of variants of uncertain significance (VUS; ∼15%) compared with American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines (∼36%). This change is attributed to unique variants with 1 benign supporting evidence (∼12%) or 1 benign strong evidence (∼4%) being classified as likely benign by the point system. Additionally, variants with conflicting/modified evidence (∼5% of 2376) are also resolved by the point system. Sub-tiering unique variants classified by the point system as VUS (<em>n</em> = 354) indicates ∼77.4% were VUS-Low (0-1 points), whereas the remaining ∼22.6% were VUS-Mid (2-3 points) and VUS-High (4-5 points).</div></div><div><h3>Conclusion</h3><div>The point system reduces the VUS rate and facilitates their sub-tiering. Future large-scale studies are warranted to explore the impact of the point system on improving VUS reporting and/or VUS clinical management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent growth-promoting effects of vosoritide in children with achondroplasia are accompanied by improvements in physical and social aspects of health-related quality of life","authors":"","doi":"10.1016/j.gim.2024.101274","DOIUrl":"10.1016/j.gim.2024.101274","url":null,"abstract":"<div><h3>Purpose</h3><div>: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia.</div></div><div><h3>Methods</h3><div>Participants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766).</div></div><div><h3>Results</h3><div>The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the Quality of Life of Short Stature Youth physical score (5.99 [19.41], caregiver reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 [22.64], respectively). Changes were greatest in participants with ≥1 SD increase in height <em>z</em>-score (physical: 11.36 [19.51], caregiver-reported [<em>n</em> = 38]; 8.48 [21.83], self-reported [<em>n</em> = 28]) (social: 5.84 [15.45] and 9.79 [22.80], respectively). To determine how domain scores may change with age in untreated persons, models were produced using observational/untreated-person data. A 1-year increase in age was associated with a change of 0.16 (SE, 0.55) and 0.16 (0.50), for caregiver-reported physical and social domain scores, respectively. Self-reported scores changed by 1.45 (0.71) and 1.92 (0.77), respectively.</div></div><div><h3>Conclusion</h3><div>These data suggest that after 3 years of treatment, vosoritide demonstrates a positive effect on physical and social functioning among children with achondroplasia, particularly in children with a more pronounced change in height <em>z</em>-score.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Genomic Counseling Model for Population-Based Sequencing: A Pre-Post Intervention Study","authors":"","doi":"10.1016/j.gim.2024.101272","DOIUrl":"10.1016/j.gim.2024.101272","url":null,"abstract":"<div><h3>Purpose</h3><div>Novel uses of genome sequencing (GS) present an opportunity for return of results to healthy individuals, prompting the need for scalable genetic counseling strategies. We evaluate the effectiveness of a genomic counseling model (GCM) and explore preferences for GS findings in the general population.</div></div><div><h3>Methods</h3><div>Participants (<em>N</em> = 466) completed GS and our GCM (digital genomics platform and group-based webinar) and indicated results preferences. Surveys were administered before (T0) and after (T1) GCM. Change in knowledge and decisional conflict (DC) were evaluated using paired-sample T and Wilcoxon tests. Factors influencing knowledge and results preferences were evaluated using linear and logistic regression models.</div></div><div><h3>Results</h3><div>Participants were 56% female, 58% white, and 53% ≥40 years of age. Mean knowledge scores increased (Limitations: 3.73 to 5.63; Benefits: 4.34 to 5.48, <em>P</em> &lt; .0001), and DC decreased (−21.9, <em>P</em> &lt; .0001) at T1 versus T0. Eighty-six percent of participants wished to learn all GS findings at T1 vs 78% at T0 (<em>P</em> &lt; .0001). Older age, negative/mixed attitudes toward genetics and greater DC were associated with change in preferences after intervention.</div></div><div><h3>Conclusion</h3><div>In a population-based cohort undergoing GS interested in learning GS findings, our GCM increased knowledge and reduced DC, illustrating the GCM’s potential effectiveness for GS counseling in the general population.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the genetic landscape of treatable inherited metabolic disorders in a large Middle Eastern biobank","authors":"","doi":"10.1016/j.gim.2024.101268","DOIUrl":"10.1016/j.gim.2024.101268","url":null,"abstract":"<div><h3>Purpose</h3><div>To date, approximately 1400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2% to 3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity.</div></div><div><h3>Methodology</h3><div>The study utilized genome sequencing data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank and sequenced by the Qatar Genome Program. The genome sequencing data were analyzed for 125 nuclear genes known to be associated with 115 treatable IMDs.</div></div><div><h3>Results</h3><div>Our study identified 253 pathogenic/likely pathogenic single-nucleotide variations associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least 1 of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively).</div></div><div><h3>Conclusion</h3><div>Population-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethical, legal, and social issues related to genetics and genomics in cancer: A scoping review and narrative synthesis","authors":"","doi":"10.1016/j.gim.2024.101270","DOIUrl":"10.1016/j.gim.2024.101270","url":null,"abstract":"<div><div>Genomics is increasingly being incorporated into models of care for cancer. Understanding the ethical, legal, and social issues (ELSI) in this domain is important for successful and equitable implementation. We aimed to identify ELSI scholarship specific to cancer control and genomics. To do this, we undertook a scoping literature review and narrative synthesis, identifying 46 articles that met inclusion criteria. Eighteen ELSI themes were developed, including (1) equity of access, which included structural barriers to testing and research, access to preventive and follow-up care, and engagement with health systems; (2) family considerations, such as an ethical obligation to disseminate relevant genomic information to at-risk family members; (3) legal considerations, including privacy and confidentiality, genetic discrimination, and the prospective duty to reclassify variants; and (4) optimizing consent processes in clinical care and research. Gaps in the literature were identified with respect to equity for people living in rural or remote areas, and how to provide ethical care within culturally, linguistically, and ethnically diverse communities, including First Nations peoples. Our findings suggest a need for a multidisciplinary approach to examining ELSI in cancer genomics beyond initial test indication and within the broader context of the mainstreaming of genomics in health care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.","authors":"Elisa Cali,Tania Quirin,Clarissa Rocca,Stephanie Efthymiou,Antonella Riva,Dana Marafi,Maha S Zaki,Mohnish Suri,Roberto Dominguez,Hasnaa M Elbendary,Shahryar Alavi,Mohamed S Abdel-Hamid,Heba Morsy,Frederic Tran Mau-Them,Mathilde Nizon,Pavel Tesner,Lukáš Ryba,Faisal Zafar,Nuzhat Rana,Nebal W Saadi,Zahra Firoozfar,Pinar Gencpinar,Bulent Unay,Canan Ustun,Ange-Line Bruel,Christine Coubes,Jennifer Stefanich,Ozlem Sezer,Emanuele Agolini,Antonio Novelli,Gessica Vasco,Donatella Lettori,Mathieu Milh,Laurent Villard,Shimriet Zeidler,Henry Opperman,Vincent Strehlow,Mahmoud Y Issa,Hebatallah El Khassab,Prem Chand,Shahnaz Ibrahim,Ali Nejad-Rashidi,Mohammad Miryounesi,Pegah Larki,Jennifer Morrison,Ingrid Cristian,Isabelle Thiffault,Nicole L Bertsch,Grace J Noh,John Pappas,Ellen Moran,Nikolaos M Marinakis,Joanne Traeger-Synodinos,Susan Hosseini,Mohammad Reza Abbaszadegan,Roseline Caumes,Lisenka E L M Vissers,Maedeh Neshatdoust,Mostafa Zohour Montazer,Elmostafa El Fahime,Christin Canavati,Lara Kamal,Moien Kanaan,Omar Askander,Victoria Voinova,Olga Levchenko,Shahzhad Haider,Sara S Halbach,Elias Rayana Maia,Salehi Mansoor,Jain Vivek,Sanjukta Tawde,Viveka Santhosh R Challa,Vykuntaraju K Gowda,Varunvenkat M Srinivasan,Lucas Alves Victor,Benito Pinero-Banos,Jennifer Hague,Heba Ahmed Ei-Awady,Adelia Maria de Miranda Henriques-Souza,Huma Arshad Cheema,Muhammad Nadeem Anjum,Sara Idkaidak,Firas Alqarajeh,Osama Atawneh,Hagar Mor-Shaked,Tamar Harel,Giovanni Zifarelli,Peter Bauer,Fernando Kok,Joao Paulo Kitajima,Fabiola Monteiro,Juliana Josahkian,Gaetan Lesca,Nicolas Chatron,Dorothe Ville,David Murphy,Jeffrey L Neul,Sureni V Mullegama,Amber Begtrup,Isabella Herman,Tadahiro Mitani,Jennifer E Posey,Chee Geap Tay,Iram Javed,Lucinda Carr,Farah Kanani,Fiona Beecroft,Lee Hane,Elsayed Abdelkreem,Milan Macek,Luciana Bispo,Marwa Abd Elmaksoud,Farzad Hashemi-Gorji,Davut Pehlivan,David J Amor,Rami Abou Jamra,Wendy K Chung,Eshan Karimiani Ghayoor,Philippe Campeau,Fowzan S Alkuraya,Alistair T Pagnamenta,Joseph Gleeson,James R Lupski,Pasquale Striano,Andres Moreno-De-Luca,Denis L J Lafontaine,Henry Houlden,Reza Maroofian","doi":"10.1016/j.gim.2024.101251","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101251","url":null,"abstract":"PURPOSEThis study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.METHODSWe identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.RESULTSBiallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing.CONCLUSIONThis study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront","authors":"","doi":"10.1016/j.gim.2024.101266","DOIUrl":"10.1016/j.gim.2024.101266","url":null,"abstract":"<div><h3>Purpose</h3><div>Diamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. <em>RPL26</em> (ribosomal protein <em>L26</em>) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition.</div></div><div><h3>Methods</h3><div>Patients carrying heterozygous <em>RPL26</em> variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34⁺ cells were studied by flow cytometry, and <em>RPL26</em> expression by quantitative reverse transcription polymerase chain reaction and immunoblotting.</div></div><div><h3>Results</h3><div>We report on 8 affected patients from 4 families. Detailed phenotyping reveals that <em>RPL26</em> is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that <em>RPL26</em> haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes.</div></div><div><h3>Conclusion</h3><div>We confirm <em>RPL26</em> as a DBS gene and expand the phenotypic spectrum of the gene and the disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}