Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.
{"title":"Ethnic-specific genetic susceptibility loci for endometriosis in Taiwanese-Han population: a genome-wide association study.","authors":"Jim Jinn-Chyuan Sheu, Wei-Yong Lin, Ting-Yuan Liu, Cherry Yin-Yi Chang, Jack Cheng, Yau-Hong Li, Chih-Mei Chen, Chung-Chen Tseng, Wendy Yarou Ding, Ching Chung, Tritium Hwang, Ping-Ho Chen, Fuu-Jen Tsai","doi":"10.1038/s10038-024-01270-5","DOIUrl":"https://doi.org/10.1038/s10038-024-01270-5","url":null,"abstract":"<p><p>Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.
{"title":"A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis.","authors":"Shota Yoneno, Kaoru Yamamoto, Kenshiro Tabata, Yuko Shimizu-Motohashi, Ayaka Tomita, Taiju Hayashi, Hiroyuki Maki, Noriko Sato, Ken Inoue, Hirotomo Saitsu, Hirofumi Komaki","doi":"10.1038/s10038-024-01268-z","DOIUrl":"https://doi.org/10.1038/s10038-024-01268-z","url":null,"abstract":"<p><p>Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Retinoblastoma (RB) is a childhood retinal neoplasm and commonly treated with cytotoxic chemotherapeutic agents. However, these therapeutic approaches often lead to diverse adverse effects. A precise molecular therapy will alleviate these side effects and offer better treatment outcomes. Over the years, kinases have become potential drug targets in cancer therapy. Hence, we aimed to investigate genetic alterations of putative kinase drug targets in RB. Targeted exome sequencing was performed on 35 RB tumors with paired blood samples using a gene panel consisting of 29 FDA-approved kinase genes. Single nucleotide variants were analyzed for pathogenicity using an in-house pipeline and copy number variations (CNVs) were detected by a depth of coverage and CNVPanelizer. The correlation between genetic changes and clinicopathological features was assessed using GraphPad Prism. Three somatic mutations, two in ERBB4 and one in EGFR were identified. Two of these mutations (ERBB4 c.C3836A & EGFR c.A1196T) were not reported earlier. CNV analysis revealed recurrent gains of ALK, MAP2K2, SRC, STK11, and FGFR3 as well as frequent losses of ATM, PI3KCA and ERBB4. Notably, nonresponsive tumors had a higher incidence of amplifications in clinically actionable genes such as ALK. Moreover, ALK gain and ATM loss were strongly correlated with optic nerve head invasion. In conclusion, our study revealed genetic alterations of druggable kinases in RB, providing preliminary insights for the exploration of kinase-targeted therapy in RB.
{"title":"Investigating druggable kinases for targeted therapy in retinoblastoma","authors":"Kumar Jeyaprakash, Manojkumar Kumaran, Usha Kim, Radhakrishnan Santhi, Veerappan Muthukkaruppan, Bharanidharan Devarajan, Ayyasamy Vanniarajan","doi":"10.1038/s10038-024-01267-0","DOIUrl":"10.1038/s10038-024-01267-0","url":null,"abstract":"Retinoblastoma (RB) is a childhood retinal neoplasm and commonly treated with cytotoxic chemotherapeutic agents. However, these therapeutic approaches often lead to diverse adverse effects. A precise molecular therapy will alleviate these side effects and offer better treatment outcomes. Over the years, kinases have become potential drug targets in cancer therapy. Hence, we aimed to investigate genetic alterations of putative kinase drug targets in RB. Targeted exome sequencing was performed on 35 RB tumors with paired blood samples using a gene panel consisting of 29 FDA-approved kinase genes. Single nucleotide variants were analyzed for pathogenicity using an in-house pipeline and copy number variations (CNVs) were detected by a depth of coverage and CNVPanelizer. The correlation between genetic changes and clinicopathological features was assessed using GraphPad Prism. Three somatic mutations, two in ERBB4 and one in EGFR were identified. Two of these mutations (ERBB4 c.C3836A & EGFR c.A1196T) were not reported earlier. CNV analysis revealed recurrent gains of ALK, MAP2K2, SRC, STK11, and FGFR3 as well as frequent losses of ATM, PI3KCA and ERBB4. Notably, nonresponsive tumors had a higher incidence of amplifications in clinically actionable genes such as ALK. Moreover, ALK gain and ATM loss were strongly correlated with optic nerve head invasion. In conclusion, our study revealed genetic alterations of druggable kinases in RB, providing preliminary insights for the exploration of kinase-targeted therapy in RB.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10-3) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10-8), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.
{"title":"Association of Crohn's disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study.","authors":"Yinan Wang, Yiming Jia, Qingyun Xu, Pinni Yang, Lulu Sun, Yi Liu, Xinyue Chang, Yu He, Mengyao Shi, Daoxia Guo, Yonghong Zhang, Zhengbao Zhu","doi":"10.1038/s10038-024-01271-4","DOIUrl":"https://doi.org/10.1038/s10038-024-01271-4","url":null,"abstract":"<p><p>Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10<sup>-3</sup>) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10<sup>-8</sup>), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1038/s10038-024-01261-6
Kaname Kojima, Shu Tadaka, Yasunobu Okamura, Kengo Kinoshita
Widely used genotype imputation methods are based on the Li and Stephens model, which assumes that new haplotypes can be represented by modifying existing haplotypes in a reference panel through mutations and recombinations. These methods use genotypes from SNP arrays as inputs to estimate haplotypes that align with the input genotypes by analyzing recombination patterns within a reference panel, and then infer unobserved variants. While these methods require reference panels in an identifiable form, their public use is limited due to privacy and consent concerns. One strategy to overcome these limitations is to use de-identified haplotype information, such as summary statistics or model parameters. Advances in deep learning (DL) offer the potential to develop imputation methods that use haplotype information in a reference-free manner by handling it as model parameters, while maintaining comparable imputation accuracy to methods based on the Li and Stephens model. Here, we provide a brief introduction to DL-based reference-free genotype imputation methods, including RNN-IMP, developed by our research group. We then evaluate the performance of RNN-IMP against widely-used Li and Stephens model-based imputation methods in terms of accuracy (R2), using the 1000 Genomes Project Phase 3 dataset and corresponding simulated Omni2.5 SNP genotype data. Although RNN-IMP is sensitive to missing values in input genotypes, we propose a two-stage imputation strategy: missing genotypes are first imputed using denoising autoencoders; RNN-IMP then processes these imputed genotypes. This approach restores the imputation accuracy that is degraded by missing values, enhancing the practical use of RNN-IMP.
广泛使用的基因型估算方法基于李氏和斯蒂芬斯模型，该模型假定新的单倍型可以通过突变和重组修改参考面板中的现有单倍型来表示。这些方法使用 SNP 阵列中的基因型作为输入，通过分析参考面板中的重组模式来估计与输入基因型一致的单倍型，然后推断未观察到的变异。虽然这些方法需要可识别形式的参考面板，但由于隐私和同意问题，其公开使用受到限制。克服这些限制的一种策略是使用去标识化的单倍型信息，如摘要统计或模型参数。深度学习（DL）的进步为开发归因方法提供了可能，这种方法通过将单倍型信息作为模型参数处理，以无参照的方式使用单倍型信息，同时保持与基于李氏和斯蒂芬斯模型的方法相当的归因准确性。在此，我们将简要介绍基于 DL 的无参照基因型估算方法，包括我们研究小组开发的 RNN-IMP。然后，我们使用 1000 基因组计划第三阶段数据集和相应的模拟 Omni2.5 SNP 基因型数据，评估了 RNN-IMP 与广泛使用的基于 Li 和 Stephens 模型的估算方法在准确率（R2）方面的性能。虽然 RNN-IMP 对输入基因型中的缺失值很敏感，但我们提出了一种两阶段归约策略：首先使用去噪自编码器归约缺失的基因型；然后 RNN-IMP 处理这些归约的基因型。这种方法恢复了因缺失值而降低的估算精度，提高了 RNN-IMP 的实际应用。
{"title":"Two-stage strategy using denoising autoencoders for robust reference-free genotype imputation with missing input genotypes","authors":"Kaname Kojima, Shu Tadaka, Yasunobu Okamura, Kengo Kinoshita","doi":"10.1038/s10038-024-01261-6","DOIUrl":"10.1038/s10038-024-01261-6","url":null,"abstract":"Widely used genotype imputation methods are based on the Li and Stephens model, which assumes that new haplotypes can be represented by modifying existing haplotypes in a reference panel through mutations and recombinations. These methods use genotypes from SNP arrays as inputs to estimate haplotypes that align with the input genotypes by analyzing recombination patterns within a reference panel, and then infer unobserved variants. While these methods require reference panels in an identifiable form, their public use is limited due to privacy and consent concerns. One strategy to overcome these limitations is to use de-identified haplotype information, such as summary statistics or model parameters. Advances in deep learning (DL) offer the potential to develop imputation methods that use haplotype information in a reference-free manner by handling it as model parameters, while maintaining comparable imputation accuracy to methods based on the Li and Stephens model. Here, we provide a brief introduction to DL-based reference-free genotype imputation methods, including RNN-IMP, developed by our research group. We then evaluate the performance of RNN-IMP against widely-used Li and Stephens model-based imputation methods in terms of accuracy (R2), using the 1000 Genomes Project Phase 3 dataset and corresponding simulated Omni2.5 SNP genotype data. Although RNN-IMP is sensitive to missing values in input genotypes, we propose a two-stage imputation strategy: missing genotypes are first imputed using denoising autoencoders; RNN-IMP then processes these imputed genotypes. This approach restores the imputation accuracy that is degraded by missing values, enhancing the practical use of RNN-IMP.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01261-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glycosylphosphatidylinositol (GPI)-anchored proteins are located at the cell surface by a covalent attachment between protein and GPI embedded in the plasma membrane. This attachment is catalyzed by GPI transamidase comprising five subunits (PIGK, PIGS, PIGT, PIGU, and GPAA1) in the endoplasmic reticulum. Loss of either subunit of GPI transamidase eliminates cell surface localization of GPI-anchored proteins. In humans, pathogenic variants in either subunit of GPI transamidase cause neurodevelopmental disorders. However, how the loss of GPI-anchored proteins triggers neurodevelopmental defects remains largely unclear. Here, we identified a novel homozygous variant of PIGK, NM_005482:c.481A > G,p. (Met161Val), in a Japanese female patient with neurodevelopmental delay, hypotonia, cerebellar atrophy, febrile seizures, hearing loss, growth impairment, dysmorphic facial features, and brachydactyly. The missense variant was found heterozygous in her father, but not in her mother. Zygosity analysis revealed that the homozygous PIGK variant in the patient was caused by paternal isodisomy. Rescue experiments using PIGK-deficient CHO cells revealed that the p.Met161Val variant of PIGK reduced GPI transamidase activity. Rescue experiments using pigk mutant zebrafish confirmed that the p.Met161Val variant compromised PIGK function in tactile-evoked motor response. We also demonstrated that axonal localization of voltage-gated sodium channels and concomitant generation of action potentials were impaired in pigk-deficient neurons in zebrafish, suggesting a link between GPI-anchored proteins and neuronal defects. Taken together, the missense p.Met161Val variant of PIGK is a novel pathogenic variant that causes the neurodevelopmental disorder.
{"title":"A novel homozygous variant of the PIGK gene caused by paternal disomy in a patient with neurodevelopmental disorder, cerebellar atrophy, and seizures.","authors":"Kenichiro Sadamitsu, Kumiko Yanagi, Yuiko Hasegawa, Yoshiko Murakami, Sean E Low, Daikun Ooshima, Yoichi Matsubara, Nobuhiko Okamoto, Tadashi Kaname, Hiromi Hirata","doi":"10.1038/s10038-024-01264-3","DOIUrl":"https://doi.org/10.1038/s10038-024-01264-3","url":null,"abstract":"<p><p>Glycosylphosphatidylinositol (GPI)-anchored proteins are located at the cell surface by a covalent attachment between protein and GPI embedded in the plasma membrane. This attachment is catalyzed by GPI transamidase comprising five subunits (PIGK, PIGS, PIGT, PIGU, and GPAA1) in the endoplasmic reticulum. Loss of either subunit of GPI transamidase eliminates cell surface localization of GPI-anchored proteins. In humans, pathogenic variants in either subunit of GPI transamidase cause neurodevelopmental disorders. However, how the loss of GPI-anchored proteins triggers neurodevelopmental defects remains largely unclear. Here, we identified a novel homozygous variant of PIGK, NM_005482:c.481A > G,p. (Met161Val), in a Japanese female patient with neurodevelopmental delay, hypotonia, cerebellar atrophy, febrile seizures, hearing loss, growth impairment, dysmorphic facial features, and brachydactyly. The missense variant was found heterozygous in her father, but not in her mother. Zygosity analysis revealed that the homozygous PIGK variant in the patient was caused by paternal isodisomy. Rescue experiments using PIGK-deficient CHO cells revealed that the p.Met161Val variant of PIGK reduced GPI transamidase activity. Rescue experiments using pigk mutant zebrafish confirmed that the p.Met161Val variant compromised PIGK function in tactile-evoked motor response. We also demonstrated that axonal localization of voltage-gated sodium channels and concomitant generation of action potentials were impaired in pigk-deficient neurons in zebrafish, suggesting a link between GPI-anchored proteins and neuronal defects. Taken together, the missense p.Met161Val variant of PIGK is a novel pathogenic variant that causes the neurodevelopmental disorder.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac channelopathies are a group of heritable disorders that affect the heart’s electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.
{"title":"Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing","authors":"Vigneshwar Senthivel, Bani Jolly, Arvinden VR, Anjali Bajaj, Rahul Bhoyar, Mohamed Imran, Harie Vignesh, Mohit Kumar Divakar, Gautam Sharma, Nitin Rai, Kapil Kumar, Jayakrishnan MP, Maniram Krishna, Jeyaprakash Shenthar, Muzaffar Ali, Shaad Abqari, Gulnaz Nadri, Vinod Scaria, Nitish Naik, Sridhar Sivasubbu","doi":"10.1038/s10038-024-01265-2","DOIUrl":"10.1038/s10038-024-01265-2","url":null,"abstract":"Cardiac channelopathies are a group of heritable disorders that affect the heart’s electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-17DOI: 10.1038/s10038-024-01257-2
Rui Dong, Ruifeng Jin, Hongwei Zhang, Haiyan Zhang, Min Xue, Yue Li, Kaihui Zhang, Yuqiang Lv, Xiaoying Li, Yi Liu, Zhongtao Gai
Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein’s pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.
{"title":"Genotypic and phenotypic characteristics of sodium channel—associated epilepsy in Chinese population","authors":"Rui Dong, Ruifeng Jin, Hongwei Zhang, Haiyan Zhang, Min Xue, Yue Li, Kaihui Zhang, Yuqiang Lv, Xiaoying Li, Yi Liu, Zhongtao Gai","doi":"10.1038/s10038-024-01257-2","DOIUrl":"10.1038/s10038-024-01257-2","url":null,"abstract":"Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein’s pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.
{"title":"Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia","authors":"Ze-Hong Zheng, Chun-Yan Cao, Bi Cheng, Ru-Ying Yuan, Yi-Heng Zeng, Zhang-Bao Guo, Yu-Sen Qiu, Wen-Qi Lv, Hui Liang, Jin-Lan Li, Wei-Xiong Zhang, Min-Kun Fang, Yu-Hao Sun, Wei Lin, Jing-Mei Hong, Shi-Rui Gan, Ning Wang, Wan-Jin Chen, Gan-Qin Du, Ling Fang","doi":"10.1038/s10038-024-01262-5","DOIUrl":"10.1038/s10038-024-01262-5","url":null,"abstract":"Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1038/s10038-024-01263-4
Li Zhang, Minna Shen, Xianhong Shu, Jingmin Zhou, Jing Ding, Huandong Lin, Baishen Pan, Chunyan Zhang, Beili Wang, Wei Guo
Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.
{"title":"The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients","authors":"Li Zhang, Minna Shen, Xianhong Shu, Jingmin Zhou, Jing Ding, Huandong Lin, Baishen Pan, Chunyan Zhang, Beili Wang, Wei Guo","doi":"10.1038/s10038-024-01263-4","DOIUrl":"10.1038/s10038-024-01263-4","url":null,"abstract":"Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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