Human Mutation最新文献

{"title":"BTKbase, Bruton Tyrosine Kinase Variant Database in X-Linked Agammaglobulinemia: Looking Back and Ahead","authors":"Gerard C. P. Schaafsma,&nbsp;Jouni Väliaho,&nbsp;Qing Wang,&nbsp;Anna Berglöf,&nbsp;Rula Zain,&nbsp;C. I. Edvard Smith,&nbsp;Mauno Vihinen","doi":"10.1155/2023/5797541","DOIUrl":"10.1155/2023/5797541","url":null,"abstract":"<div>\u0000 <p>BTKbase is an international database for disease-causing variants in Bruton tyrosine kinase (<i>BTK</i>) leading to X-linked agammaglobulinemia (XLA), a rare primary immunodeficiency of antibody production. BTKbase was established in 1994 as one of the first publicly available variation databases. The number of cases has more than doubled since the last update; it now contains information for 2310 DNA variants in 2291 individuals. 1025 of the DNA variants are unique. The human genome contains more than 500 protein kinases, among which BTK has the largest number of unique disease-causing variants. The current version of BTKbase has numerous novel features: the database has been reformatted, it has moved to LOVD database management system, it has been internally harmonized, etc. Systematics and standardization have been increased, including Variation Ontology annotations for variation types. There are some regions with lower than expected variation frequency and some hotspots for variations. BTKbase contains, in addition to variant descriptions at DNA, RNA and protein levels, also laboratory parameters and clinical features for many patients. BTKbase has served clinical and research communities in the diagnosis of XLA cases and provides general insight into effects of variations, especially in signalling pathways. Amino acid substitutions and their effects were investigated, predicted, and visualized at 3D level in the protein domains. BTKbase is freely available.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5797541","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49472020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Common PKD1 p.(Ile3167Phe) Variant Is Hypomorphic and Associated with Very Early Onset, Biallelic Polycystic Kidney Disease","authors":"Miranda Durkie,&nbsp;Christopher M. Watson,&nbsp;Peter Winship,&nbsp;Anne-Cecile Hogg,&nbsp;Rodney Nyanhete,&nbsp;Sharon Cooley,&nbsp;Manoj K. Valluru,&nbsp;Charles Shaw-Smith,&nbsp;Coralie Bingham,&nbsp;Mark Gilchrist,&nbsp;Janna Kenny,&nbsp;Genomics England Research Consortium,&nbsp;Albert C. M. Ong","doi":"10.1155/2023/5597005","DOIUrl":"10.1155/2023/5597005","url":null,"abstract":"<div>\u0000 <p>Biallelic <i>PKD1</i> variants, including hypomorphic variants, can cause very early onset polycystic kidney disease (VEO-PKD). A family with unexplained recurrent VEO-PKD and neonatal demise in one dizygotic twin was referred for clinical testing. Further individuals with the putative hypomorphic <i>PKD1</i> variant, p.(Ile3167Phe), were identified from the UK 100,000 genomes project (100 K), UK Biobank (UKBB), and a review of the literature. We identified a likely pathogenic <i>PKD1</i> missense paternal variant and the putative hypomorphic <i>PKD1</i> variant from the unaffected mother in the deceased twin but only the paternal <i>PKD1</i> variant in the surviving dizygotic twin. Analysis of 100 K cases identified a second family with two siblings with similar biallelic inheritance who presented at birth with VEO-PKD and reached kidney failure in their teens unlike other affected relatives. Finally, a survey of 618 UKBB cases confirmed that adult patients monoallelic for <i>PKD1</i> p.(Ile3167Phe) had normal kidney function. Our data reveals that p.(Ile3167Phe) is the second most common <i>PKD1</i> hypomorphic variant identified and is neutral in heterozygosity but is associated with VEO-PKD when inherited <i>in trans</i> with a pathogenic <i>PKD1</i> variant. Care should be taken to ensure that it is not automatically filtered from sequence data for VEO cases.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5597005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49326034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splicing Analysis of MYO5B Noncanonical Variants in Patients with Low Gamma-Glutamyltransferase Cholestasis","authors":"Li Wang,&nbsp;Yi-Ling Qiu,&nbsp;Kuerbanjiang Abuduxikuer,&nbsp;Neng-Li Wang,&nbsp;Zhong-Die Li,&nbsp;Ye Cheng,&nbsp;Yi Lu,&nbsp;Xin-Bao Xie,&nbsp;Qing-He Xing,&nbsp;Jian-She Wang","doi":"10.1155/2023/8848362","DOIUrl":"10.1155/2023/8848362","url":null,"abstract":"<div>\u0000 <p>Biallelic <i>MYO5B</i> variants have been associated with familial intrahepatic cholestasis (FIC) with low serum gamma-glutamyltransferase (GGT). Intronic or synonymous variants outside of canonical splice sites (hereinafter referred to as noncanonical variants) with uncertain significance were identified in <i>MYO5B</i> posing a challenge in clinical interpretation. This study is aimed at assessing the effects of these variants on premessenger RNA (pre-mRNA) splicing to improve recognition of pathogenic spliceogenic variants in <i>MYO5B</i> and better characterize the <i>MYO5B</i> genetic variation spectrum. Disease-associated <i>MYO5B</i> noncanonical variants were collected from the literature or newly identified low GGT cholestasis patients. <i>In silico</i> splicing predictions were performed to prioritize potential pathogenic variants. Minigene splicing assays were performed to determine their splicing patterns, with confirmation by blood RNA analysis in one case. Eleven (five novel) noncanonical variants with uncertain significance were identified. Minigene splicing assays revealed that three variants (c.2090+3A&gt;T, c.2414+5G&gt;T, and c.613-11G&gt;A) caused complete aberrations, five variants (c.2349A&gt;G/p.(=), c.4221G&gt;A/p.(=), c.1322+5G&gt;A, c.1669-35A&gt;C, and c.3045+3A&gt;T) caused predominant aberrations, and three variants (c.4852+11A&gt;G, c.455+8T&gt;C, and c.2415-6C&gt;G) had no effect on pre-mRNA splicing. Patient-derived RNA analysis showed consistent results. Based on our results, eight variants were reclassified as likely pathogenic and three as likely benign. Combining the clinical features and the above analysis, the diagnosis of <i>MYO5B</i>-associated FIC could be made in three new patients. In conclusion, we characterized the splicing patterns of <i>MYO5B</i> noncanonical variants and suggest that RNA analysis should be routinely included in clinical diagnostics to provide essential evidence for the interpretation of variants.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/8848362","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47549997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive LOVD Database for Fatty Acid Oxidation Disorders in Chinese Populations","authors":"Ting Zhang,&nbsp;Zinan Yu,&nbsp;Lingwei Hu,&nbsp;Chao Zhang,&nbsp;Haixia Miao,&nbsp;Rulai Yang,&nbsp;Ming Qi,&nbsp;Benqing Wu,&nbsp;Xinwen Huang","doi":"10.1155/2023/5493978","DOIUrl":"10.1155/2023/5493978","url":null,"abstract":"<div>\u0000 <p>Fatty acid oxidation disorders (FAODs) are a group of rare, autosomal recessive, metabolic disorders with clinical symptoms from mild types of fatigue, muscle weakness to severe types of hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis, especially during prolonged fasting, exercise, and illness. There are eleven diseases caused by thirteen FAOD genes (<i>SLC22A5</i>, <i>ETFDH</i>, <i>ETFA</i>, <i>ETFB</i>, <i>SLC25A20</i>, <i>ACADS</i>, <i>ACADM</i>, <i>ACADVL</i>, <i>ACAT1</i>, <i>CPT1A</i>, <i>CPT2</i>, <i>HADHA</i>, and <i>HADHB</i>) which are specific enzymes or transport proteins involved in the mitochondrial catabolism of fatty acids. We built the LOVD database for FAODs focused on the Chinese population, in which we recorded all the reported variants by literature peer review. In addition, the unpublished variant data of patients from Zhejiang province were also incorporated into the database. Currently, a total of 538 unique variants have been recorded. We also compared the incidence of high-frequency variants of certain FAOD genes among different populations. The database would provide the guidance for genetic screening of Chinese patients.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5493978","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48536362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal","authors":"Hannah D. West,&nbsp;Mark Nellist,&nbsp;Rutger W. W. Brouwer,&nbsp;Mirjam C. G. N. van den Hout-van Vroonhoven,&nbsp;Luiz Gustavo Dufner de Almeida,&nbsp;Femke Hendriks,&nbsp;Peter Elfferich,&nbsp;Meera Raja,&nbsp;Peter Giles,&nbsp;Rosa M. Alfano,&nbsp;Angela Peron,&nbsp;Yves Sznajer,&nbsp;Liesbeth De Waele,&nbsp;Anna Jansen,&nbsp;Marije Koopmans,&nbsp;Anneke Kievit,&nbsp;Laura S. Farach,&nbsp;Hope Northrup,&nbsp;Julian R. Sampson,&nbsp;Laura E. Thomas,&nbsp;Wilfred F. J. van IJcken","doi":"10.1155/2023/4899372","DOIUrl":"10.1155/2023/4899372","url":null,"abstract":"<div>\u0000 <p>Tuberous sclerosis complex (TSC) is caused by inactivating variants in <i>TSC1</i> and <i>TSC2</i>. Somatic mosaicism, as well as the size and complexity of the <i>TSC1</i> and <i>TSC2</i> loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve <i>TSC1</i> and <i>TSC2</i> variant detection, we screened the <i>TSC1</i> and <i>TSC2</i> genomic regions using targeted HaloPlex custom capture and next-generation sequencing (NGS) in genomic DNA isolated from peripheral blood of individuals with definite, possible or suspected TSC in whom no disease-associated variant had been identified by previous diagnostic genetic testing. We obtained &gt;95% target region coverage at a read depth of 20 and &gt;50% coverage at a read depth of 300 and identified inactivating <i>TSC1</i> or <i>TSC2</i> variants in 83/155 individuals (54%); 65/113 (58%) with clinically definite TSC and 18/42 (43%) with possible or suspected TSC. These included 19 individuals with deep intronic variants and 54 likely cases of mosaicism (variant allele frequency 1-28%; median 7%). In 13 cases (8%), we identified a variant of uncertain significance (VUS). Targeted genomic NGS of <i>TSC1</i> and <i>TSC2</i> increases the yield of inactivating variants found in individuals with suspected TSC.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4899372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42260693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Characterization of Novel Lunatic Fringe Variants in Spondylocostal Dysostosis Type-III with Scoliosis","authors":"Parker Wengryn,&nbsp;Karina da Costa Silveira,&nbsp;Connor Oborn,&nbsp;Carrie-Lynn Soltys,&nbsp;Alexander Beke,&nbsp;Inara Chacon-Fonseca,&nbsp;Nadirah Damseh,&nbsp;Marco Quesada Rodriguez,&nbsp;Ramses Badilla-Porras,&nbsp;Peter Kannu","doi":"10.1155/2023/5989733","DOIUrl":"10.1155/2023/5989733","url":null,"abstract":"<div>\u0000 <p>Scoliosis affects over four million Americans, with most cases having an idiopathic cause. Pathogenic variants in the <i>LUNATIC FRINGE</i> (<i>LFNG</i>) gene can cause spondylocostal dysostosis type-III (SCD3), which is a rare skeletal dysplasia characterized by the absence, fusion, or partial development of vertebrae and ribs. Acute restrictive lung disease and scoliosis may also be present in some cases. The variability in symptoms suggests that there may be other underlying pathological mechanisms that are yet to be discovered. We conducted an analysis of two novel <i>LFNG</i> variants, c.766G&gt;A (p.G256S) and c.521G&gt;A (p.R174H), that were observed in a patient with SCD3 phenotype and scoliosis. Characterizing these variants can help us better understand the relationship between genotype and phenotype. We assessed both variants for impaired glycosyltransferase activity, subcellular mislocalization, and aberrant pre-proprotein processing. Our results indicate that the p.G256S variant is enzymatically nonfunctional, while the p.R174H variant is functionally less effective. Both variants were correctly localized and processed. Our findings suggest that the hypomorphic variant (p.R174H) may have partially improved the patient’s stature, as evidenced by a lower arm span-to-height ratio, increased height, and more vertebrae. However, this variant did not appear to have any effect on the severity of vertebral malformations, including scoliosis. Further research is necessary to determine the extent to which variations in LFNG activity affect the presentation of SCD3.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5989733","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42688441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models","authors":"Xintong Zhu,&nbsp;Xiaoyin Tan,&nbsp;Junwen Wang,&nbsp;Limeng Dai,&nbsp;Jia Li,&nbsp;Xingying Guan,&nbsp;Ziyi Wang,&nbsp;Mao Zhang,&nbsp;Jun Hu,&nbsp;Yun Bai,&nbsp;Hong Guo","doi":"10.1155/2023/4834423","DOIUrl":"10.1155/2023/4834423","url":null,"abstract":"<div>\u0000 <p>Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the <i>ERLIN2</i> gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of <i>ERLIN2</i> heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of <i>ERLIN2</i> in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in <i>ERLIN2</i> is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4834423","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43543879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)","authors":"Kevin Uguen,&nbsp;Chandran Ka,&nbsp;Gwenaelle Collod-Béroud,&nbsp;Marlène Le Tertre,&nbsp;Julie Guellec,&nbsp;Claude Férec,&nbsp;Christophe Béroud,&nbsp;Isabelle Callebaut,&nbsp;Gérald Le Gac","doi":"10.1155/2023/5162256","DOIUrl":"10.1155/2023/5162256","url":null,"abstract":"<div>\u0000 <p>SLC40A1 is the sole iron export protein reported in mammals and is a key player in both cellular and systemic iron homeostasis. This unique iron exporter, which belongs to the major facilitator superfamily, is predominantly regulated by the hyposideremic hormone hepcidin. SLC40A1 dysfunction causes ferroportin disease, and autosomal dominant iron overload disorder characterized by cellular iron retention, principally in reticuloendothelial cells, correlating with high serum ferritin and low to normal transferrin saturation. Resistant to hepcidin, SLC40A1 mutations are rather associated with elevated plasma iron and parenchymal iron deposition, a condition that resembles <i>HFE</i>-related hemochromatosis and is associated with more clinical complications. With very few exceptions, only missense variations are reported at the <i>SLC40A1</i> locus; this situation increasingly limits the establishment of pathogenicity. In this mutation update, we provide a comprehensive review of all the pathogenic or likely pathogenic variants, variants of unknown significance, and benign or likely benign <i>SLC40A1</i> variants. The classification is essentially determined using functional, structural, segregation, and recurrence data. We furnish new information on genotype-phenotype correlations for loss-of-function, gain-of-function, and other <i>SLC40A1</i> variants, confirming the existence of wide clinical heterogeneity and the potential for misdiagnosis. All information is recorded in a locus-specific online database.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5162256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41360231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Balanced Translocation Disrupting JAG1 Identified by Optical Genomic Mapping in Suspected Alagille Syndrome","authors":"Yi-Qiong Zhang,&nbsp;Peng-Fei Gao,&nbsp;Jing-Min Yang,&nbsp;Jing Zhang,&nbsp;Yu-Lan Lu,&nbsp;Jian-She Wang","doi":"10.1155/2023/5396281","DOIUrl":"10.1155/2023/5396281","url":null,"abstract":"<div>\u0000 <p>We report the clinical and genetic features of a Han Chinese boy who presented with disease suspect for Alagille syndrome (ALGS). Multiple genetic analyses (panel sequencing, multiplex-ligation-dependent probe amplification, and whole genome sequencing) failed to uncover a causative variant. Optical genomic mapping detected a reciprocal translocation between chromosomes 4 and 20, interrupting <i>JAG1</i>. Long-range polymerase chain reaction and targeted sequencing identified the exact breakpoints. Sanger sequencing and reanalysis of genome sequencing raw data further confirmed the result. This translocation is expected to generate aberrant <i>JAG1</i> transcripts that lead to complete loss of <i>JAG1</i> expression. This is the first t(4;20)(q22.1;p12.2) balanced translocation detected by optical genomic mapping and characterized at base-pair resolution in ALGS. Our approach permitted precise diagnosis and genetic counseling.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5396281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42609430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency and Functional Characterization of RUNX1 Germline Variants in Myeloid Neoplasms","authors":"Nikolaj Juul Nitschke,&nbsp;Marwa Almosailleakh,&nbsp;Yiyuan Niu,&nbsp;Jakob Werner Hansen,&nbsp;Klas Raaschou-Jensen,&nbsp;Jakob Schmidt Jespersen,&nbsp;Marianne Tang Severinsen,&nbsp;Anne Stidsholt Roug,&nbsp;Morten Frödin,&nbsp;Joachim Lütken Weischenfeldt,&nbsp;Mette Klarskov Andersen,&nbsp;Kirsten Grønbæk","doi":"10.1155/2023/4738660","DOIUrl":"10.1155/2023/4738660","url":null,"abstract":"<div>\u0000 <p>Current estimates suggest that up to 10% of patients with myeloid neoplasms (MN) harbor variants associated with a germline predisposition. A pathogenic variant in the runt-related transcription factor 1 gene (<i>RUNX1</i>) is a frequent cause of germline predisposition to MN. <i>RUNX1</i> variants detected in tumor tissue at a VAF close to 50% are potentially germline and causative of <i>RUNX1</i> familial platelet disorder with associated myeloid malignancies. Previous studies have found germline <i>RUNX1</i> variants in 3% of patients with acute myeloid leukemia; however, the frequency of germline <i>RUNX1</i> variants in less advanced myeloid neoplasms has not been examined. We screened 590 patients suspected of MN, excluding myeloproliferative neoplasms, for germline variants in <i>RUNX1</i>. We found <i>RUNX1</i> variants in 83 patients (14%) by targeted sequencing of tumor tissue. In 40 patients (6.8%), the VAF of <i>RUNX1</i> was above 30%. In 32 of the 40 patients, skin biopsies were available and used for Sanger sequencing to assess the germline status. Two of the tested variants (6.3%) were confirmed as germline, and both variants were curated as variants of unknown significance. To further explore the pathogenicity of these variants, we implemented a novel CRISPR-Select functional genetic assay. The assay demonstrated a profound effect on proliferation in K562 cells for a known pathogenic variant but no effect for the two germline variants detected in the study. We therefore propose that both germline variants are classified as likely benign. In this study, we show that <i>RUNX1</i> germline variants are rare in Danish patients with MN and use a novel assay for functional classification of germline <i>RUNX1</i> variants.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4738660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47740432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}