Pub Date : 2024-06-28DOI: 10.1038/s41525-024-00417-9
Niccolò Rossi, Najeeb Syed, Alessia Visconti, Elbay Aliyev, Sarah Berry, Mafalda Bourbon, Tim D Spector, Pirro G Hysi, Khalid A Fakhro, Mario Falchi
Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10-12) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.
{"title":"Rare variants at KCNJ2 are associated with LDL-cholesterol levels in a cross-population study.","authors":"Niccolò Rossi, Najeeb Syed, Alessia Visconti, Elbay Aliyev, Sarah Berry, Mafalda Bourbon, Tim D Spector, Pirro G Hysi, Khalid A Fakhro, Mario Falchi","doi":"10.1038/s41525-024-00417-9","DOIUrl":"https://doi.org/10.1038/s41525-024-00417-9","url":null,"abstract":"<p><p>Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10<sup>-12</sup>) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"36"},"PeriodicalIF":4.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469662","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}
Pub Date : 2024-06-19DOI: 10.1038/s41525-024-00418-8
Anne Van Arsdale, Lauren Turker, Yoke-Chen Chang, Joshua Gould, Bryan Harmon, Elaine C Maggi, Olga Meshcheryakova, Maxwell P Brown, Dana Luong, Koenraad Van Doorslaer, Mark H Einstein, Dennis Y S Kuo, Deyou Zheng, Brian J Haas, Jack Lenz, Cristina Montagna
HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.
部分外阴癌与人乳头瘤病毒感染有关。通过杂交捕获和 DNA 测序,13 例外阴癌中有 5 例检测到了 HPV DNA。在这五例中,有三例将HPV16 DNA整合到了人类DNA中。这些插入物位于人类 NCKAP1、C5orf67 和 LRP1B 的内含子中。NCKAP1和C5orf67中的整合片段两侧是人类DNA中的短直接重复序列,这与HPV DNA插入到中止、交错、核酸内切的位点是一致的。C5orf67 中的插入物是一个 36 kbp 的人类-HPV-异源-癌变 DNA,要么是染色体外的环状结构,要么是人类基因组内的串联重复。人类环化/重复交界处是以单核苷酸分辨率确定的。整合后的病毒 DNA 片段都保留了完整的上游调控区以及邻近的病毒 E6 和 E7 致癌基因。RNA 测序显示,从整合的病毒 DNA 中持续转录的 HPV 基因只有 E7 和 E6*I。另外两个HPV DNA+肿瘤有合并感染,但没有整合的证据。HPV阳性和HPV阴性外阴癌表现出截然不同的人类全基因表达模式,这与之前观察到的HPV阳性和HPV阴性宫颈癌和口咽癌之间的差异部分重叠。大部分差异表达基因涉及免疫系统功能。因此,外阴癌的转录和 HPV DNA 整合与其他 HPV 阳性癌症相似。这项研究强调了杂交捕获技术与DNA和RNA测序技术相结合在确定广泛的HPV类型、确定病毒DNA的人类基因组整合状态以及阐明其结构方面的威力。
{"title":"Structure and transcription of integrated HPV DNA in vulvar carcinomas.","authors":"Anne Van Arsdale, Lauren Turker, Yoke-Chen Chang, Joshua Gould, Bryan Harmon, Elaine C Maggi, Olga Meshcheryakova, Maxwell P Brown, Dana Luong, Koenraad Van Doorslaer, Mark H Einstein, Dennis Y S Kuo, Deyou Zheng, Brian J Haas, Jack Lenz, Cristina Montagna","doi":"10.1038/s41525-024-00418-8","DOIUrl":"10.1038/s41525-024-00418-8","url":null,"abstract":"<p><p>HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"35"},"PeriodicalIF":4.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427333","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}
Pub Date : 2024-05-30DOI: 10.1038/s41525-024-00419-7
Sadeep Shrestha, Howard W Wiener, Sabrina Chowdhury, Hidemi Kajimoto, Vinodh Srinivasasainagendra, Olga A Mamaeva, Ujval N Brahmbhatt, Dolena Ledee, Yung R Lau, Luz A Padilla, Jake Y Chen, Nagib Dahdah, Hemant K Tiwari, Michael A Portman
Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.
{"title":"Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease.","authors":"Sadeep Shrestha, Howard W Wiener, Sabrina Chowdhury, Hidemi Kajimoto, Vinodh Srinivasasainagendra, Olga A Mamaeva, Ujval N Brahmbhatt, Dolena Ledee, Yung R Lau, Luz A Padilla, Jake Y Chen, Nagib Dahdah, Hemant K Tiwari, Michael A Portman","doi":"10.1038/s41525-024-00419-7","DOIUrl":"10.1038/s41525-024-00419-7","url":null,"abstract":"<p><p>Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"34"},"PeriodicalIF":5.3,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180307","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}
Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG△4-10 deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG△4-10 deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.
猪失禁症(IP)是一种罕见的X连锁显性神经外胚层发育不良症,主要影响女性。唯一已知的致病基因是IKBKG,最常见的遗传原因是两个MER67B重复序列之间的重组导致IKBKG△4-10缺失。由于存在一个高度同源的非致病假基因IKBKGP1,因此检测IKBKG的变异具有挑战性。在本研究中,我们采用基于单管长片段读数(stLFR)测序的策略和专门的分析流水线,在四名 IP 患者中成功鉴定出了四个致病变体。其中发现了三个帧移变异(c.519-3_519dupCAGG、c.1167dupC 和 c.700dupT),随后通过桑格测序进行了验证。值得注意的是,c.519-3_519dupCAGG 在 IKBKG 和 IKBKGP1 中都被发现,而其他两个变异只在功能基因中被检测到。在一名患者中发现并证实了IKBKG△4-10缺失。这些结果表明,所提出的策略可以识别潜在的致病变体,并区分它们是来自于IKBKG还是其假基因。因此,这种策略可以成为一种有效的 IKBKG 基因检测方法。通过对全基因组的全面了解,该方法还能探索与 IP 潜在相关的其他基因。此外,该策略还能帮助人们深入了解因假基因而导致检测困难的其他疾病。
{"title":"An efficient molecular genetic testing strategy for incontinentia pigmenti based on single-tube long fragment read sequencing.","authors":"Min Chen, Mei-Hua Tan, Jiao Liu, Yan-Mei Yang, Jia-Ling Yu, Li-Juan He, Ying-Zhi Huang, Yi-Xi Sun, Ye-Qing Qian, Kai Yan, Min-Yue Dong","doi":"10.1038/s41525-024-00421-z","DOIUrl":"10.1038/s41525-024-00421-z","url":null,"abstract":"<p><p>Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG<sup>△4-10</sup> deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG<sup>△4-10</sup> deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"32"},"PeriodicalIF":5.3,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175683","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}
Pub Date : 2024-05-29DOI: 10.1038/s41525-024-00415-x
Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne
To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
{"title":"Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.","authors":"Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne","doi":"10.1038/s41525-024-00415-x","DOIUrl":"10.1038/s41525-024-00415-x","url":null,"abstract":"<p><p>To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"33"},"PeriodicalIF":5.3,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175684","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}
Pub Date : 2024-05-27DOI: 10.1038/s41525-024-00416-w
Blake M Hauser, Yuyang Luo, Anusha Nathan, Ahmad Al-Moujahed, Demetrios G Vavvas, Jason Comander, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Gaurav D Gaiha, Elizabeth J Rossin
Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.
{"title":"Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.","authors":"Blake M Hauser, Yuyang Luo, Anusha Nathan, Ahmad Al-Moujahed, Demetrios G Vavvas, Jason Comander, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Gaurav D Gaiha, Elizabeth J Rossin","doi":"10.1038/s41525-024-00416-w","DOIUrl":"10.1038/s41525-024-00416-w","url":null,"abstract":"<p><p>Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"31"},"PeriodicalIF":4.7,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158960","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}
Pub Date : 2024-05-17DOI: 10.1038/s41525-024-00414-y
Jane W Liang, Kurt D Christensen, Robert C Green, Peter Kraft
Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.
{"title":"Evaluating the utility of multi-gene, multi-disease population-based panel testing accounting for uncertainty in penetrance estimates.","authors":"Jane W Liang, Kurt D Christensen, Robert C Green, Peter Kraft","doi":"10.1038/s41525-024-00414-y","DOIUrl":"https://doi.org/10.1038/s41525-024-00414-y","url":null,"abstract":"<p><p>Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"30"},"PeriodicalIF":5.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958610","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}
Pub Date : 2024-05-04DOI: 10.1038/s41525-024-00409-9
Lonneke Haer-Wigman, Amber den Ouden, Ronny Derks, Maria M. van Genderen, Dorien Lugtenberg, Joke Verheij, Raymon Vijzelaar, Helger G. Yntema, Lisenka E. L. M. Vissers, Kornelia Neveling
{"title":"Reply to: Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects","authors":"Lonneke Haer-Wigman, Amber den Ouden, Ronny Derks, Maria M. van Genderen, Dorien Lugtenberg, Joke Verheij, Raymon Vijzelaar, Helger G. Yntema, Lisenka E. L. M. Vissers, Kornelia Neveling","doi":"10.1038/s41525-024-00409-9","DOIUrl":"https://doi.org/10.1038/s41525-024-00409-9","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"45 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140839125","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}
Pub Date : 2024-05-04DOI: 10.1038/s41525-024-00406-y
Bernd Wissinger, Britta Baumann, Elena Buena-Atienza, Caspar Gross, Susanne Kohl
{"title":"Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects","authors":"Bernd Wissinger, Britta Baumann, Elena Buena-Atienza, Caspar Gross, Susanne Kohl","doi":"10.1038/s41525-024-00406-y","DOIUrl":"https://doi.org/10.1038/s41525-024-00406-y","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"53 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838990","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}
Pub Date : 2024-04-06DOI: 10.1038/s41525-024-00408-w
Ali AlMail, Ahmed Jamjoom, Amy Pan, Min Yi Feng, Vann Chau, Alissa M. D’Gama, Katherine Howell, Nicole S. Y. Liang, Amy McTague, Annapurna Poduri, Kimberly Wiltrout, Anne S. Bassett, John Christodoulou, Lucie Dupuis, Peter Gill, Tess Levy, Paige Siper, Zornitza Stark, Jacob A. S. Vorstman, Catherine Diskin, Natalie Jewitt, Danielle Baribeau, Gregory Costain
Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.
{"title":"Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions","authors":"Ali AlMail, Ahmed Jamjoom, Amy Pan, Min Yi Feng, Vann Chau, Alissa M. D’Gama, Katherine Howell, Nicole S. Y. Liang, Amy McTague, Annapurna Poduri, Kimberly Wiltrout, Anne S. Bassett, John Christodoulou, Lucie Dupuis, Peter Gill, Tess Levy, Paige Siper, Zornitza Stark, Jacob A. S. Vorstman, Catherine Diskin, Natalie Jewitt, Danielle Baribeau, Gregory Costain","doi":"10.1038/s41525-024-00408-w","DOIUrl":"https://doi.org/10.1038/s41525-024-00408-w","url":null,"abstract":"<p>Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (<i>n</i> = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"68 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591631","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}