NPJ Genomic Medicine最新文献

Clinical and genetic characterization of patients with late onset Wilson's disease.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-24 DOI: 10.1038/s41525-024-00459-z

Wenming Yang, Yue Yang, Han Wang, Jiuxiang Wang, Shijie Zhang

引用次数: 0

Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts. 通过对人类肾囊肿进行深度测序发现常染色体显性多囊肾的体细胞突变。

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00452-6

Amali C Mallawaarachchi, Yvonne Hort, Laura Wedd, Kitty Lo, Sarah Senum, Mojgan Toumari, Wenhan Chen, Mike Utsiwegota, Jane Mawson, Scott Leslie, Jerome Laurence, Lyndal Anderson, Paul Snelling, Robert Salomon, Gopala K Rangan, Timothy Furlong, John Shine, Mark J Cowley

{"title":"Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.","authors":"Amali C Mallawaarachchi, Yvonne Hort, Laura Wedd, Kitty Lo, Sarah Senum, Mojgan Toumari, Wenhan Chen, Mike Utsiwegota, Jane Mawson, Scott Leslie, Jerome Laurence, Lyndal Anderson, Paul Snelling, Robert Salomon, Gopala K Rangan, Timothy Furlong, John Shine, Mark J Cowley","doi":"10.1038/s41525-024-00452-6","DOIUrl":"https://doi.org/10.1038/s41525-024-00452-6","url":null,"abstract":"Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation. We used unique molecular identifiers, high-depth massively parallel sequencing and custom analysis techniques to identify somatic second-hit mutations in 24 whole cysts from disparate regions of six human ADPKD kidneys, utilising replicate samples and orthogonal confirmation. Average depth of coverage of 1166 error-corrected reads for PKD1 and 539 reads for PKD2 was obtained. 58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant. We demonstrate that low-frequency somatic mutations are detectable in a proportion of cysts from end-stage ADPKD human kidneys. Further studies are required to understand the drivers of this somatic mutation.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"69"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00450-8

Simone Montalbano, Morten Dybdahl Krebs, Anders Rosengren, Morteza Vaez, Kajsa-Lotta Georgii Hellberg, Preben B Mortensen, Anders D Børglum, Daniel H Geschwind, Armin Raznahan, Wesley K Thompson, Dorte Helenius, Thomas Werge, Andrés Ingason

{"title":"Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology.","authors":"Simone Montalbano, Morten Dybdahl Krebs, Anders Rosengren, Morteza Vaez, Kajsa-Lotta Georgii Hellberg, Preben B Mortensen, Anders D Børglum, Daniel H Geschwind, Armin Raznahan, Wesley K Thompson, Dorte Helenius, Thomas Werge, Andrés Ingason","doi":"10.1038/s41525-024-00450-8","DOIUrl":"10.1038/s41525-024-00450-8","url":null,"abstract":"The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions. We used the iPSYCH2015 case-cohort sample to obtain unbiased estimates of the prevalence of NRXN1 deletions and their associated risk of autism, schizophrenia, depression, and ADHD. Most exon-disrupting deletions affected exons specific to the alpha isoform, and almost half of the non-exonic deletions represented a previously reported segregating founder deletion. Carriage of exon-disrupting NRXN1 deletions was associated with a threefold and twofold increased risk of autism and ADHD, respectively, whereas no significantly increased risk of depression or schizophrenia was observed. Our results highlight the importance of using population-based samples in genetic association studies.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"67"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Implementing genomic newborn screening as an effective public health intervention: sidestepping the hype and criticism.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00451-7

Jan M Friedman

引用次数: 0

Functional assessment of IDUA variants of uncertain significance identified by newborn screening.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00457-1

Seok-Ho Yu, Francyne Kubaski, Gavin Arno, Whitney Phinney, Tim C Wood, Heather Flanagan-Steet, Laura M Pollard, Richard Steet

{"title":"Functional assessment of IDUA variants of uncertain significance identified by newborn screening.","authors":"Seok-Ho Yu, Francyne Kubaski, Gavin Arno, Whitney Phinney, Tim C Wood, Heather Flanagan-Steet, Laura M Pollard, Richard Steet","doi":"10.1038/s41525-024-00457-1","DOIUrl":"https://doi.org/10.1038/s41525-024-00457-1","url":null,"abstract":"With the expansion of newborn screening efforts for MPS disorders, the number of identified variants of uncertain significance in IDUA continues to increase. To better define functional consequences of identified IDUA variants, we developed a HEK293-based expression platform that can be used to determine the relative specific activity of variant α-iduronidases by combining a fluorescence-based activity assay and semi-quantitative western blotting. We employed the current platform to characterize over thirty different IDUA variants, including known benign and pathogenic variants, as well as multiple variants of uncertain significance identified through newborn screening. This analysis allowed the stratification of variant enzymes based on their relative specific activity, and uncovered distinct effects of the different variants on enzyme folding, processing, and stability. While relative specific activity serves as a useful first-level test for enzyme function, our observations reinforce the need for secondary analyses of enzyme function to fully assess variant pathogenicity.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"68"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Efficient reinterpretation of rare disease cases using Exomiser.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-18 DOI: 10.1038/s41525-024-00456-2

Letizia Vestito, Julius O B Jacobsen, Susan Walker, Valentina Cipriani, Nomi L Harris, Melissa A Haendel, Christopher J Mungall, Peter Robinson, Damian Smedley

{"title":"Efficient reinterpretation of rare disease cases using Exomiser.","authors":"Letizia Vestito, Julius O B Jacobsen, Susan Walker, Valentina Cipriani, Nomi L Harris, Melissa A Haendel, Christopher J Mungall, Peter Robinson, Damian Smedley","doi":"10.1038/s41525-024-00456-2","DOIUrl":"https://doi.org/10.1038/s41525-024-00456-2","url":null,"abstract":"Whole genome sequencing has transformed rare disease research; however, 50-80% of rare disease patients remain undiagnosed after such testing. Regular reanalysis can identify new diagnoses, especially in newly discovered disease-gene associations, but efficient tools are required to support clinical interpretation. Exomiser, a phenotype-driven variant prioritisation tool, fulfils this role; within the 100,000 Genomes Project (100kGP), diagnoses were identified after reanalysis in 463 (2%) of 24,015 unsolved patients after previous analysis for variants in known disease genes. However, extensive manual interpretation was required. This led us to develop a reanalysis strategy to efficiently reveal candidates from recent disease gene discoveries or newly designated pathogenic/likely pathogenic variants. Optimal settings to highlight new candidates from Exomiser reanalysis were identified with high recall (82%) and precision (88%) when including Exomiser's automated ACMG/AMP classifier, which correctly converted 92% of variants from unknown significance to pathogenic/likely pathogenic. In conclusion, Exomiser efficiently reinterprets previously unsolved cases.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"65"},"PeriodicalIF":4.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-read genome sequencing resolves complex genomic rearrangements in rare genetic syndromes.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-18 DOI: 10.1038/s41525-024-00454-4

Iftekhar A Showpnil, Maria E Hernandez Gonzalez, Swetha Ramadesikan, Mohammad Marhabaie, Allison Daley, Leeran Dublin-Ryan, Matthew T Pastore, Umamaheswaran Gurusamy, Jesse M Hunter, Brandon S Stone, Dennis W Bartholomew, Kandamurugu Manickam, Anthony R Miller, Richard K Wilson, Rolf W Stottmann, Daniel C Koboldt

{"title":"Long-read genome sequencing resolves complex genomic rearrangements in rare genetic syndromes.","authors":"Iftekhar A Showpnil, Maria E Hernandez Gonzalez, Swetha Ramadesikan, Mohammad Marhabaie, Allison Daley, Leeran Dublin-Ryan, Matthew T Pastore, Umamaheswaran Gurusamy, Jesse M Hunter, Brandon S Stone, Dennis W Bartholomew, Kandamurugu Manickam, Anthony R Miller, Richard K Wilson, Rolf W Stottmann, Daniel C Koboldt","doi":"10.1038/s41525-024-00454-4","DOIUrl":"https://doi.org/10.1038/s41525-024-00454-4","url":null,"abstract":"Long-read sequencing can often overcome the deficiencies in routine microarray or short-read technologies in detecting complex genomic rearrangements. Here we used Pacific Biosciences circular consensus sequencing to resolve complex rearrangements in two patients with rare genetic anomalies. Copy number variants (CNVs) identified by clinical microarray -chr8p deletion and chr8q duplication in patient 1, and interstitial deletions of chr18q in patient 2-were suggestive of underlying rearrangements. Long-read genome sequencing not only confirmed these CNVs but also revealed their genomic structures. In patient 1, we resolved a novel recombinant chromosome 8 (Rec8)-like rearrangement with a 3.43 Mb chr8q terminal duplication that was linked to a 7.25-8.21 Mb chr8p terminal deletion. In patient 2, we uncovered a novel complex rearrangement involving a 1.17 Mb rearranged segment and four interstitial deletions ranging from 9 bp to 12.39 Mb. Our results underscore the diversity of clinically relevant structural rearrangements and the power of long-read sequencing in unraveling their nuanced architectures.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"66"},"PeriodicalIF":4.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-04 DOI: 10.1038/s41525-024-00444-6

Ashlesha Gogate, Kiran Kaur, Raida Khalil, Mahmoud Bashtawi, Mary Ann Morris, Kimberly Goodspeed, Patricia Evans, Maria H Chahrour

{"title":"The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort.","authors":"Ashlesha Gogate, Kiran Kaur, Raida Khalil, Mahmoud Bashtawi, Mary Ann Morris, Kimberly Goodspeed, Patricia Evans, Maria H Chahrour","doi":"10.1038/s41525-024-00444-6","DOIUrl":"10.1038/s41525-024-00444-6","url":null,"abstract":"Autism spectrum disorder (ASD) comprises neurodevelopmental disorders with wide variability in genetic causes and phenotypes, making it challenging to pinpoint causal genes. We performed whole exome sequencing on a modest, ancestrally diverse cohort of 195 families, including 754 individuals (222 with ASD), and identified 38,834 novel private variants. In 68 individuals with ASD (~30%), we identified 92 potentially pathogenic variants in 73 known genes, including BCORL1, CDKL5, CHAMP1, KAT6A, MECP2, and SETD1B. Additionally, we identified 158 potentially pathogenic variants in 120 candidate genes, including DLG3, GABRQ, KALRN, KCTD16, and SLC8A3. We also found 34 copy number variants in 31 individuals overlapping known ASD loci. Our work expands the catalog of ASD genetics by identifying hundreds of variants across diverse ancestral backgrounds, highlighting convergence on nervous system development and signal transduction. These findings provide insights into the genetic underpinnings of ASD and inform molecular diagnosis and potential therapeutic targets.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"62"},"PeriodicalIF":4.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780680","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}

引用次数: 0

Comparative transcriptomic, epigenomic and immunological analyses identify drivers of disparity in high-grade serous ovarian cancer.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-02 DOI: 10.1038/s41525-024-00448-2

Hao Huang, Russel Keathley, Ujin Kim, Horacio Cardenas, Ping Xie, Jianjun Wei, Ernst Lengyel, Kenneth P Nephew, Guangyuan Zhao, Zhen Fu, Emma L Barber, Masha Kocherginsky, Victoria Bae-Jump, Bin Zhang, Daniela Matei

{"title":"Comparative transcriptomic, epigenomic and immunological analyses identify drivers of disparity in high-grade serous ovarian cancer.","authors":"Hao Huang, Russel Keathley, Ujin Kim, Horacio Cardenas, Ping Xie, Jianjun Wei, Ernst Lengyel, Kenneth P Nephew, Guangyuan Zhao, Zhen Fu, Emma L Barber, Masha Kocherginsky, Victoria Bae-Jump, Bin Zhang, Daniela Matei","doi":"10.1038/s41525-024-00448-2","DOIUrl":"10.1038/s41525-024-00448-2","url":null,"abstract":"Black women face the highest mortality-to-incidence ratio from high grade serous ovarian cancer (HGSOC). This study investigated biological differences in HGSOC tumors from Black vs. White women. HGSOC from 35 Black and 31 White patients were analyzed by Infinium Methyation-EPIC array and RNA sequencing. 191 CpG sites were differentially methylated (FDR < 0.05, β value change> 10%) and 277 genes were differentially expressed (FDR < 0.05). Gene Ontology identified enriched pathways related to DNA damage response, p53/apoptosis signaling, and cholesterol/lipid metabolism directly connected with genes like INSR, FOXA1 and FOXB1. INSR and FOXA1 knockdown enhanced cisplatin sensitivity and inhibited cell proliferation and colony formation. Tumors from Black patients were infiltrated by fewer CD4+ naïve and regulatory T-cells. Overall, differences in DNA methylation, transcriptomic profiles and immune cell infiltration were detected in tumors from Black vs. White patients. Further investigation is warranted into how these differences may affect treatment response and outcomes in Black women.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"64"},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770760","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}

引用次数: 0

Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes.

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2024-12-02 DOI: 10.1038/s41525-024-00441-9

Courtney E French, Nancy C Andrews, Alan H Beggs, Philip M Boone, Catherine A Brownstein, Maya Chopra, Janet Chou, Wendy K Chung, Alissa M D'Gama, Ryan N Doan, Darius Ebrahimi-Fakhari, Richard D Goldstein, Mira Irons, Christina Jacobsen, Margaret Kenna, Ted Lee, Jill A Madden, Amar J Majmundar, Nina Mann, Sarah U Morton, Annapurna Poduri, Adrienne G Randolph, Amy E Roberts, Stephanie Roberts, Matthew G Sampson, Diane D Shao, Wanqing Shao, Aditi Sharma, Eliot Shearer, Akiko Shimamura, Scott B Snapper, Siddharth Srivastava, Jay R Thiagarajah, Mary C Whitman, Monica H Wojcik, Shira Rockowitz, Piotr Sliz

{"title":"Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes.","authors":"Courtney E French, Nancy C Andrews, Alan H Beggs, Philip M Boone, Catherine A Brownstein, Maya Chopra, Janet Chou, Wendy K Chung, Alissa M D'Gama, Ryan N Doan, Darius Ebrahimi-Fakhari, Richard D Goldstein, Mira Irons, Christina Jacobsen, Margaret Kenna, Ted Lee, Jill A Madden, Amar J Majmundar, Nina Mann, Sarah U Morton, Annapurna Poduri, Adrienne G Randolph, Amy E Roberts, Stephanie Roberts, Matthew G Sampson, Diane D Shao, Wanqing Shao, Aditi Sharma, Eliot Shearer, Akiko Shimamura, Scott B Snapper, Siddharth Srivastava, Jay R Thiagarajah, Mary C Whitman, Monica H Wojcik, Shira Rockowitz, Piotr Sliz","doi":"10.1038/s41525-024-00441-9","DOIUrl":"10.1038/s41525-024-00441-9","url":null,"abstract":"Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"60"},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770761","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}

引用次数: 0