NPJ Genomic Medicine最新文献_第8页

The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death. 遗传性心脏病和不明原因心脏性猝死中剪接破坏变异的负担。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-10-11 DOI: 10.1038/s41525-023-00373-w

Emma S Singer, Joshua Crowe, Mira Holliday, Julia C Isbister, Sean Lal, Natalie Nowak, Laura Yeates, Charlotte Burns, Sulekha Rajagopalan, Ivan Macciocca, Ingrid King, Julie Wacker, Jodie Ingles, Robert G Weintraub, Christopher Semsarian, Richard D Bagnall

{"title":"The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death.","authors":"Emma S Singer, Joshua Crowe, Mira Holliday, Julia C Isbister, Sean Lal, Natalie Nowak, Laura Yeates, Charlotte Burns, Sulekha Rajagopalan, Ivan Macciocca, Ingrid King, Julie Wacker, Jodie Ingles, Robert G Weintraub, Christopher Semsarian, Richard D Bagnall","doi":"10.1038/s41525-023-00373-w","DOIUrl":"10.1038/s41525-023-00373-w","url":null,"abstract":"There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"29"},"PeriodicalIF":5.3,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41207223","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

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy. SLCO5A1和突触组装基因对青少年肌阵挛性癫痫的冲动性有贡献。

IF 4.7 2区医学

NPJ Genomic Medicine Pub Date : 2023-09-28 DOI: 10.1038/s41525-023-00370-z

Delnaz Roshandel, Eric J Sanders, Amy Shakeshaft, Naim Panjwani, Fan Lin, Amber Collingwood, Anna Hall, Katherine Keenan, Celine Deneubourg, Filippo Mirabella, Simon Topp, Jana Zarubova, Rhys H Thomas, Inga Talvik, Marte Syvertsen, Pasquale Striano, Anna B Smith, Kaja K Selmer, Guido Rubboli, Alessandro Orsini, Ching Ching Ng, Rikke S Møller, Kheng Seang Lim, Khalid Hamandi, David A Greenberg, Joanna Gesche, Elena Gardella, Choong Yi Fong, Christoph P Beier, Danielle M Andrade, Heinz Jungbluth, Mark P Richardson, Annalisa Pastore, Manolis Fanto, Deb K Pal, Lisa J Strug

{"title":"SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.","authors":"Delnaz Roshandel, Eric J Sanders, Amy Shakeshaft, Naim Panjwani, Fan Lin, Amber Collingwood, Anna Hall, Katherine Keenan, Celine Deneubourg, Filippo Mirabella, Simon Topp, Jana Zarubova, Rhys H Thomas, Inga Talvik, Marte Syvertsen, Pasquale Striano, Anna B Smith, Kaja K Selmer, Guido Rubboli, Alessandro Orsini, Ching Ching Ng, Rikke S Møller, Kheng Seang Lim, Khalid Hamandi, David A Greenberg, Joanna Gesche, Elena Gardella, Choong Yi Fong, Christoph P Beier, Danielle M Andrade, Heinz Jungbluth, Mark P Richardson, Annalisa Pastore, Manolis Fanto, Deb K Pal, Lisa J Strug","doi":"10.1038/s41525-023-00370-z","DOIUrl":"10.1038/s41525-023-00370-z","url":null,"abstract":"Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"28"},"PeriodicalIF":4.7,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10539321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41138710","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

Curated incidence of lysosomal storage diseases from the Taiwan Biobank. 台湾生物库的溶酶体储存病的治愈发病率。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-09-23 DOI: 10.1038/s41525-023-00372-x

Meng-Ju Melody Tsai, Miao-Zi Hung, Yi-Lin Lin, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu

{"title":"Curated incidence of lysosomal storage diseases from the Taiwan Biobank.","authors":"Meng-Ju Melody Tsai, Miao-Zi Hung, Yi-Lin Lin, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu","doi":"10.1038/s41525-023-00372-x","DOIUrl":"10.1038/s41525-023-00372-x","url":null,"abstract":"Lysosomal storage diseases (LSDs) are a group of metabolic disorders resulting from a deficiency in one of the lysosomal hydrolases. Most LSDs are inherited in an autosomal or X-linked recessive manner. As LSDs are rare, their true incidence in Taiwan remains unknown. In this study, we used high-coverage whole-genome sequencing data from 1,495 Taiwanese individuals obtained from the Taiwan Biobank. We found 3826 variants in 71 genes responsible for autosomal recessive LSDs. We first excluded benign variants by allele frequency and other criteria. As a result, 270 variants were considered disease-causing. We curated these variants using published guidelines from the American College of Medical Genetics and Genomics (ACMG). Our results revealed a combined incidence rate of 13 per 100,000 (conservative estimation by pathologic and likely pathogenic variants; 95% CI 6.92-22.23) to 94 per 100,000 (extended estimation by the inclusion of variants of unknown significance; 95% CI 75.96-115.03) among 71 autosomal recessive disease-associated genes. The conservative estimations were similar to those in published clinical data. No disease-causing mutations were found for 18 other diseases; thus, these diseases are likely extremely rare in Taiwan. The study results are important for designing screening and treatment methods for LSDs in Taiwan and demonstrate the importance of mutation curation to avoid overestimating disease incidences from genomic data.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"27"},"PeriodicalIF":5.3,"publicationDate":"2023-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41138237","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

DNA methylation profiles in individuals with rare, atypical 7q11.23 CNVs correlate with GTF2I and GTF2IRD1 copy number. 罕见的非典型7q11.23 CNVs个体的DNA甲基化谱与GTF2I和GTF2IRD1拷贝数相关。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-09-14 DOI: 10.1038/s41525-023-00368-7

Emma Strong, Carolyn B Mervis, Elaine Tam, Colleen A Morris, Bonita P Klein-Tasman, Shelley L Velleman, Lucy R Osborne

{"title":"DNA methylation profiles in individuals with rare, atypical 7q11.23 CNVs correlate with GTF2I and GTF2IRD1 copy number.","authors":"Emma Strong, Carolyn B Mervis, Elaine Tam, Colleen A Morris, Bonita P Klein-Tasman, Shelley L Velleman, Lucy R Osborne","doi":"10.1038/s41525-023-00368-7","DOIUrl":"10.1038/s41525-023-00368-7","url":null,"abstract":"Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"25"},"PeriodicalIF":5.3,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10617438","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

A pan-sarcoma landscape of telomeric content shows that alterations in RAD51B and GID4 are associated with higher telomeric content. 端粒含量的泛肉瘤图谱显示，RAD51B和GID4的改变与更高的端粒含量有关。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-09-14 DOI: 10.1038/s41525-023-00369-6

Radwa Sharaf, Dexter X Jin, John Grady, Christine Napier, Ericka Ebot, Garrett M Frampton, Lee A Albacker, David M Thomas, Meagan Montesion

{"title":"A pan-sarcoma landscape of telomeric content shows that alterations in RAD51B and GID4 are associated with higher telomeric content.","authors":"Radwa Sharaf, Dexter X Jin, John Grady, Christine Napier, Ericka Ebot, Garrett M Frampton, Lee A Albacker, David M Thomas, Meagan Montesion","doi":"10.1038/s41525-023-00369-6","DOIUrl":"10.1038/s41525-023-00369-6","url":null,"abstract":"Tumor cells need to activate a telomere maintenance mechanism, enabling limitless replication. The bulk of evidence supports that sarcomas predominantly use alternative lengthening of telomeres (ALT) mechanism, commonly associated with alterations in ATRX and DAXX. In our dataset, only 12.3% of sarcomas harbored alterations in these genes. Thus, we checked for the presence of other genomic determinants of high telomeric content in sarcomas. Our dataset consisted of 13555 sarcoma samples, sequenced as a part of routine clinical care on the FoundationOne®Heme platform. We observed a median telomeric content of 622.3 telomeric reads per GC-matched million reads (TRPM) across all samples. In agreement with previous studies, telomeric content was significantly higher in ATRX altered and POT1 altered sarcomas. We further observed that sarcomas with alterations in RAD51B or GID4 were enriched in samples with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B and soft tissue sarcoma (not otherwise specified, nos) for GID4, Furthermore, RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of functional redundancy. Our results propose a role played by RAD51B and GID4 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this critical pathway in tumorigenesis.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"26"},"PeriodicalIF":5.3,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10320933","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

Structural variation of the coding and non-coding human pharmacogenome. 编码与非编码人类药物基因组的结构变异。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-09-08 DOI: 10.1038/s41525-023-00371-y

Roman Tremmel, Yitian Zhou, Matthias Schwab, Volker M Lauschke

{"title":"Structural variation of the coding and non-coding human pharmacogenome.","authors":"Roman Tremmel, Yitian Zhou, Matthias Schwab, Volker M Lauschke","doi":"10.1038/s41525-023-00371-y","DOIUrl":"10.1038/s41525-023-00371-y","url":null,"abstract":"Genetic variants in drug targets and genes encoding factors involved in drug absorption, distribution, metabolism and excretion (ADME) can have pronounced impacts on drug pharmacokinetics, response, and toxicity. While the landscape of genetic variability at the level of single nucleotide variants (SNVs) has been extensively studied in these pharmacogenetic loci, their structural variation is only poorly understood. Thus, we systematically analyzed the genetic structural variability across 908 pharmacogenes (344 ADME genes and 564 drug targets) based on publicly available whole genome sequencing data from 10,847 unrelated individuals. Overall, we extracted 14,984 distinct structural variants (SVs) ranging in size from 50 bp to 106 Mb. Each individual harbored on average 10.3 and 1.5 SVs with putative functional effects that affected the coding regions of ADME genes and drug targets, respectively. In addition, by cross-referencing pharmacogenomic SVs with experimentally determined binding data of 224 transcription factors across 130 cell types, we identified 1276 non-coding SVs that overlapped with gene regulatory elements. Based on these data, we estimate that non-coding structural variants account for 22% of the genetically encoded pharmacogenomic variability. Combined, these analyses provide the first comprehensive map of structural variability across pharmacogenes, derive estimates for the functional impact of non-coding SVs and incentivize the incorporation of structural genomic data into personalized drug response predictions.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"24"},"PeriodicalIF":5.3,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10562313","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: 1

Pan-cancer atlas of somatic core and linker histone mutations. 体细胞核心和连接蛋白突变的泛癌症图谱。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-08-28 DOI: 10.1038/s41525-023-00367-8

Erin R Bonner, Adam Dawood, Heather Gordish-Dressman, Augustine Eze, Surajit Bhattacharya, Sridevi Yadavilli, Sabine Mueller, Sebastian M Waszak, Javad Nazarian

{"title":"Pan-cancer atlas of somatic core and linker histone mutations.","authors":"Erin R Bonner, Adam Dawood, Heather Gordish-Dressman, Augustine Eze, Surajit Bhattacharya, Sridevi Yadavilli, Sabine Mueller, Sebastian M Waszak, Javad Nazarian","doi":"10.1038/s41525-023-00367-8","DOIUrl":"10.1038/s41525-023-00367-8","url":null,"abstract":"Recent genomic data points to a growing role for somatic mutations altering core histone and linker histone-encoding genes in cancer. However, the prevalence and the clinical and biological implications of histone gene mutations in malignant tumors remain incompletely defined. To address these knowledge gaps, we analyzed somatic mutations in 88 linker and core histone genes across 12,743 tumors from pediatric, adolescent and young adult (AYA), and adult cancer patients. We established a pan-cancer histone mutation atlas contextualized by patient age, survival outcome, and tumor location. Overall, 11% of tumors harbored somatic histone mutations, with the highest rates observed among chondrosarcoma (67%), pediatric high-grade glioma (pHGG, >60%), and lymphoma (>30%). Previously unreported histone mutations were discovered in pHGG and other pediatric brain tumors, extending the spectrum of histone gene alterations associated with these cancers. Histone mutation status predicted patient survival outcome in tumor entities including adrenocortical carcinoma. Recurrent pan-cancer histone mutation hotspots were defined and shown to converge on evolutionarily conserved and functional residues. Moreover, we studied histone gene mutations in 1700 pan-cancer cell lines to validate the prevalence and spectrum of histone mutations seen in primary tumors and derived histone-associated drug response profiles, revealing candidate drugs targeting histone mutant cancer cells. This study presents the first-of-its-kind atlas of both core and linker histone mutations across pediatric, AYA, and adult cancers, providing a framework by which specific cancers may be redefined in the context of histone and chromatin alterations.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"23"},"PeriodicalIF":5.3,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10120004","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: 1

IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma. 邻近NHEJ1内含子内的IHH增强子变异可引起小眼性贫血、眼失和结肠瘤。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-08-14 DOI: 10.1038/s41525-023-00364-x

Ohad Wormser, Yonatan Perez, Vadim Dolgin, Bahman Kamali, Jared A Tangeman, Libe Gradstein, Yuval Yogev, Noam Hadar, Ofek Freund, Max Drabkin, Daniel Halperin, Inbar Irron, Erika Grajales-Esquivel, Katia Del Rio-Tsonis, Ramon Y Birnbaum, Gidon Akler, Ohad S Birk

{"title":"IHH enhancer variant within neighboring NHEJ1 intron causes microphthalmia anophthalmia and coloboma.","authors":"Ohad Wormser, Yonatan Perez, Vadim Dolgin, Bahman Kamali, Jared A Tangeman, Libe Gradstein, Yuval Yogev, Noam Hadar, Ofek Freund, Max Drabkin, Daniel Halperin, Inbar Irron, Erika Grajales-Esquivel, Katia Del Rio-Tsonis, Ramon Y Birnbaum, Gidon Akler, Ohad S Birk","doi":"10.1038/s41525-023-00364-x","DOIUrl":"10.1038/s41525-023-00364-x","url":null,"abstract":"Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"22"},"PeriodicalIF":5.3,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10015040","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

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine. 了解尼曼-皮克病C型(NPC)的表型变异性:对精准医学的需求。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-08-11 DOI: 10.1038/s41525-023-00365-w

Macarena Las Heras, Benjamín Szenfeld, Rami A Ballout, Emanuele Buratti, Silvana Zanlungo, Andrea Dardis, Andrés D Klein

引用次数: 2

Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases. 家族共分离和长读序列在遗传性视网膜疾病中重新分类不确定意义变异的新作用。

IF 5.3 2区医学

NPJ Genomic Medicine Pub Date : 2023-08-10 DOI: 10.1038/s41525-023-00366-9

Pankhuri Gupta, Kenji Nakamichi, Alyssa C Bonnell, Ryan Yanagihara, Nick Radulovich, Fuki M Hisama, Jennifer R Chao, Debarshi Mustafi

{"title":"Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases.","authors":"Pankhuri Gupta, Kenji Nakamichi, Alyssa C Bonnell, Ryan Yanagihara, Nick Radulovich, Fuki M Hisama, Jennifer R Chao, Debarshi Mustafi","doi":"10.1038/s41525-023-00366-9","DOIUrl":"10.1038/s41525-023-00366-9","url":null,"abstract":"Phasing genetic variants is essential in determining those that are potentially disease-causing. In autosomal recessive inherited retinal diseases (IRDs), reclassification of variants of uncertain significance (VUS) can provide a genetic diagnosis in indeterminate compound heterozygote cases. We report four cases in which familial co-segregation demonstrated a VUS resided in trans to a known pathogenic variant, which in concert with other supporting criteria, led to the reclassification of the VUS to likely pathogenic, thereby providing a genetic diagnosis in each case. We also demonstrate in a simplex patient without access to family members for co-segregation analysis that targeted long-read sequencing can provide haplotagged variant calling. This can elucidate if variants reside in trans and provide phase of genetic variants from the proband alone without parental testing. This emerging method can alleviate the bottleneck of haplotype analysis in cases where genetic testing of family members is unfeasible to provide a complete genetic diagnosis.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"20"},"PeriodicalIF":5.3,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9975638","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