Human Genetics最新文献

{"title":"N6-methyladenosine modified lncRNAs signature for stratification of biochemical recurrence in prostate cancer.","authors":"Yingke Liang, Wenjun Yin, Zhouda Cai, Hongwei Luo, Qinwei Liu, Chuanfan Zhong, Jiahong Chen, Zhuoyuan Lin, Yaqiang Huang, Zhenguo Liang, Junhong Deng, Weide Zhong, Chao Cai, Jianming Lu","doi":"10.1007/s00439-023-02603-8","DOIUrl":"10.1007/s00439-023-02603-8","url":null,"abstract":"<p><p>Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"857-874"},"PeriodicalIF":3.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.","authors":"Rebecca E Andersen, Ibrahim F Alkuraya, Abna Ajeesh, Tyler Sakamoto, Elijah L Mena, Sami S Amr, Hila Romi, Margaret A Kenna, Caroline D Robson, Ellen S Wilch, Katarena Nalbandian, Raul Piña-Aguilar, Christopher A Walsh, Cynthia C Morton","doi":"10.1007/s00439-024-02693-y","DOIUrl":"10.1007/s00439-024-02693-y","url":null,"abstract":"<p><p>In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"921-938"},"PeriodicalIF":3.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trisomy silencing by XIST: translational prospects and challenges.","authors":"Khusali Gupta, Jan T Czerminski, Jeanne B Lawrence","doi":"10.1007/s00439-024-02651-8","DOIUrl":"10.1007/s00439-024-02651-8","url":null,"abstract":"<p><p>XIST RNA is heavily studied for its role in fundamental epigenetics and X-chromosome inactivation; however, the translational potential of this singular RNA has been much less explored. This article combines elements of a review on XIST biology with our perspective on the translational prospects and challenges of XIST transgenics. We first briefly review aspects of XIST RNA basic biology that are key to its translational relevance, and then discuss recent efforts to develop translational utility of XIST for chromosome dosage disorders, particularly Down syndrome (DS). Remarkably, it was shown in vitro that expression of an XIST transgene inserted into one chromosome 21 can comprehensively silence that chromosome and \"dosage compensate\" Trisomy 21, the cause of DS. Here we summarize recent findings and discuss potential paths whereby ability to induce \"trisomy silencing\" can advance translational research for new therapeutic strategies. Despite its common nature, the underlying biology for various aspects of DS, including cell types and pathways impacted (and when), is poorly understood. Recent studies show that an inducible iPSC system to dosage-correct chromosome 21 can provide a powerful approach to unravel the cells and pathways directly impacted, and the developmental timing, information key to design pharmacotherapeutics. In addition, we discuss prospects of a more far-reaching and challenging possibility that XIST itself could be developed into a therapeutic agent, for targeted cellular \"chromosome therapy\". A few rare case studies of imbalanced X;autosome translocations indicate that natural XIST can rescue an otherwise lethal trisomy. The potential efficacy of XIST transgenes later in development faces substantial biological and technical challenges, although recent findings are encouraging, and technology is rapidly evolving. Hence, it is compelling to consider the transformative possibility that XIST-mediated chromosome therapy may ultimately be developed, for specific pathologies seen in DS, or other duplication disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"843-855"},"PeriodicalIF":3.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human ABL1 deficiency syndrome (HADS) is a recognizable syndrome distinct from ABL1-related congenital heart defects and skeletal malformations syndrome.","authors":"Lama AlAbdi, Teresa Neuhann, Eva-Christina Prott, Ulrike Schön, Firdous Abdulwahab, Eissa Faqeih, Fowzan S Alkuraya","doi":"10.1007/s00439-024-02677-y","DOIUrl":"10.1007/s00439-024-02677-y","url":null,"abstract":"<p><p>Germline gain of function variants in the oncogene ABL1 cause congenital heart defects and skeletal malformations (CHDSKM) syndrome. Whether a corresponding ABL1 deficiency disorder exists in humans remains unknown although developmental defects in mice deficient for Abl1 support this notion. Here, we describe two multiplex consanguineous families, each segregating a different homozygous likely loss of function variant in ABL1. The associated phenotype is multiple congenital malformations and distinctive facial dysmorphism that are opposite in many ways to CHDSKM. We suggest that a tight balance of ABL1 activity is required during embryonic development and that both germline gain of function and loss of function variants result in distinctively different allelic congenital malformation disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"739-745"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.","authors":"Niels Vos, Sadegheh Haghshenas, Liselot van der Laan, Perle K M Russel, Kathleen Rooney, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Saskia M Maas, Lisenka E L M Vissers, Bert B A de Vries, Rolph Pfundt, Mariet W Elting, Johanna M van Hagen, Nienke E Verbeek, Marjolijn C J Jongmans, Phillis Lakeman, Lynne Rumping, Danielle G M Bosch, Antonio Vitobello, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot, Aurore Garde, Marjolaine Willems, David Genevieve, Gaël Nicolas, Tiffany Busa, Annick Toutain, Marion Gérard, Varoona Bizaoui, Bertrand Isidor, Giuseppe Merla, Maria Accadia, Charles E Schwartz, Katrin Ounap, Mariëtte J V Hoffer, Marjan M Nezarati, Marie-José H van den Boogaard, Matthew L Tedder, Curtis Rogers, Alfredo Brusco, Giovanni B Ferrero, Marta Spodenkiewicz, Richard Sidlow, Alessandro Mussa, Slavica Trajkova, Emma McCann, Henry J Mroczkowski, Sandra Jansen, Laura Donker-Kaat, Floor A M Duijkers, Kyra E Stuurman, Marcel M A M Mannens, Mariëlle Alders, Peter Henneman, Susan M White, Bekim Sadikovic, Mieke M van Haelst","doi":"10.1007/s00439-024-02679-w","DOIUrl":"10.1007/s00439-024-02679-w","url":null,"abstract":"<p><p>Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"761-773"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes.","authors":"Viviana Tritto, Paola Bettinaglio, Eleonora Mangano, Claudia Cesaretti, Federica Marasca, Chiara Castronovo, Roberta Bordoni, Cristina Battaglia, Veronica Saletti, Valeria Ranzani, Beatrice Bodega, Marica Eoli, Federica Natacci, Paola Riva","doi":"10.1007/s00439-024-02683-0","DOIUrl":"10.1007/s00439-024-02683-0","url":null,"abstract":"<p><p>NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two \"likely pathogenic\" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients' follow-up.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"775-795"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies.","authors":"Elisabetta Di Fede, Antonella Lettieri, Esi Taci, Silvia Castiglioni, Stefano Rebellato, Chiara Parodi, Elisa Adele Colombo, Paolo Grazioli, Federica Natacci, Paola Marchisio, Lidia Pezzani, Grazia Fazio, Donatella Milani, Valentina Massa, Cristina Gervasini","doi":"10.1007/s00439-024-02675-0","DOIUrl":"10.1007/s00439-024-02675-0","url":null,"abstract":"<p><p>Histone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, 3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (HDAC4, HDAC6 and HDAC8) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a de novo frameshift variant in HDAC2 gene. We then investigated its molecular effects in lymphoblastoid cell lines (LCLs) derived from the patient compared to LCLs from healthy donors (HD). As the variant was predicted to be likely pathogenetic and to affect the sequence of nuclear localization signal, we performed immunocytochemistry and lysates fractionation, observing a nuclear mis-localization of HDAC2 compared to HD LCLs. In addition, HDAC2 total protein abundance resulted altered in patient, and we found that newly identified variant in HDAC2 affects also acetylation levels, with significant difference in acetylation pattern among patient #249, HD and RSTS cells and in expression of a known molecular target. Remarkably, RNA-seq performed on #249, HD and RSTS cells shows differentially expressed genes (DEGs) common to #249 and RSTS. Interestingly, our reported patient was clinically diagnosed with RSTS, a chromatinopathy which known causative genes encode for enzymes antagonizing HDACs. These results support the role of HDAC2 as causative gene for chromatinopathies, strengthening the genotype-phenotype correlations in this relevant group of disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"747-759"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STRAS:a snakemake pipeline for genome-wide short tandem repeats annotation and score.","authors":"Mengna Zhang","doi":"10.1007/s00439-024-02662-5","DOIUrl":"10.1007/s00439-024-02662-5","url":null,"abstract":"<p><p>High-throughput whole genome sequencing (WGS) is clinically used in finding single nucleotide variants and small indels. Several bioinformatics tools are developed to call short tandem repeats (STRs) copy numbers from WGS data, such as ExpansionHunter denovo, GangSTR and HipSTR. However, expansion disorders are rare and it is hard to find candidate expansions in single patient sequencing data with ~ 800,000 STRs calls. In this paper I describe a snakemake pipeline for genome-wide STRs Annotation and Score (STRAS) using a Random Forest (RF) model to predict pathogenicity. The predictor was validated by benchmark data from Clinvar and PUBMED. True positive rate was 93.8%. True negative rate was 98.0%.Precision was 98.6% and recall rate was 93.8%. F1-score was 0.961. Sensitivity was 93.8% and specificity was 99.6%. These results showed STRAS could be a useful tool for clinical researchers to find STR loci of interest and filter out neutral STRs. STRAS is freely available at https://github.com/fancheyu5/STRAS .</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"735-738"},"PeriodicalIF":5.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-ancestry genetic architecture and prediction for cholesterol traits.","authors":"Md Moksedul Momin, Xuan Zhou, Elina Hyppönen, Beben Benyamin, S Hong Lee","doi":"10.1007/s00439-024-02660-7","DOIUrl":"10.1007/s00439-024-02660-7","url":null,"abstract":"<p><p>While cholesterol is essential, a high level of cholesterol is associated with the risk of cardiovascular diseases. Genome-wide association studies (GWASs) have proven successful in identifying genetic variants that are linked to cholesterol levels, predominantly in white European populations. However, the extent to which genetic effects on cholesterol vary across different ancestries remains largely unexplored. Here, we estimate cross-ancestry genetic correlation to address questions on how genetic effects are shared across ancestries. We find significant genetic heterogeneity between ancestries for cholesterol traits. Furthermore, we demonstrate that single nucleotide polymorphisms (SNPs) with concordant effects across ancestries for cholesterol are more frequently found in regulatory regions compared to other genomic regions. Indeed, the positive genetic covariance between ancestries is mostly driven by the effects of the concordant SNPs, whereas the genetic heterogeneity is attributed to the discordant SNPs. We also show that the predictive ability of the concordant SNPs is significantly higher than the discordant SNPs in the cross-ancestry polygenic prediction. The list of concordant SNPs for cholesterol is available in GWAS Catalog. These findings have relevance for the understanding of shared genetic architecture across ancestries, contributing to the development of clinical strategies for polygenic prediction of cholesterol in cross-ancestral settings.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"635-648"},"PeriodicalIF":3.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.","authors":"Alejandro Ferrer, Patrick Duffy, Rory J Olson, Michael A Meiners, Laura Schultz-Rogers, Erica L Macke, Stephanie Safgren, Joel A Morales-Rosado, Margot A Cousin, Gavin R Oliver, David Rider, Megan Williams, Pavel N Pichurin, David R Deyle, Eva Morava, Ralitza H Gavrilova, Radhika Dhamija, Klass J Wierenga, Brendan C Lanpher, Dusica Babovic-Vuksanovic, Charu Kaiwar, Carolyn R Vitek, Tammy M McAllister, Myra J Wick, Lisa A Schimmenti, Konstantinos N Lazaridis, Filippo Pinto E Vairo, Eric W Klee","doi":"10.1007/s00439-024-02664-3","DOIUrl":"10.1007/s00439-024-02664-3","url":null,"abstract":"<p><p>Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"649-666"},"PeriodicalIF":5.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}