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":"69 10","pages":"511-518"},"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":"10.1038/s10038-024-01264-3","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 11","pages":"553-563"},"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":"69 9","pages":"455-465"},"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":"69 9","pages":"441-453"},"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":"69 9","pages":"433-440"},"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":"69 9","pages":"425-431"},"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}
Pub Date : 2024-06-04DOI: 10.1038/s10038-024-01259-0
Natsuhiko Kumasaka
Gaussian processes (GPs) are a powerful and useful approach for modelling nonlinear phenomena in various scientific fields, including genomics and genetics. This review focuses on the application of GPs in genetic association mapping. The aim is to identify genetic variants that alter gene regulation along continuous cellular states at the molecular level, as well as disease susceptibility over time and space at the population level. The challenges and opportunities in this field are also addressed.
{"title":"Genetic association mapping leveraging Gaussian processes","authors":"Natsuhiko Kumasaka","doi":"10.1038/s10038-024-01259-0","DOIUrl":"10.1038/s10038-024-01259-0","url":null,"abstract":"Gaussian processes (GPs) are a powerful and useful approach for modelling nonlinear phenomena in various scientific fields, including genomics and genetics. This review focuses on the application of GPs in genetic association mapping. The aim is to identify genetic variants that alter gene regulation along continuous cellular states at the molecular level, as well as disease susceptibility over time and space at the population level. The challenges and opportunities in this field are also addressed.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"505-510"},"PeriodicalIF":2.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01259-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246844","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}
Pub Date : 2024-06-01DOI: 10.1038/s10038-024-01258-1
Ji-Hee Yoon, Soojin Hwang, Hyunwoo Bae, Dohyung Kim, Go Hun Seo, June-Young Koh, Young Seok Ju, Hyo-Sang Do, Soyoung Kim, Gu-Hwan Kim, Ja Hye Kim, Jin-Ho Choi, Beom Hee Lee
Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. The median age at clinical diagnosis was 18.5 months (IQR 7–58 months), and the median follow-up duration was 80.5 months (IQR 48–112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. This study enhances the understanding of the clinical and genetic characteristics of KS.
{"title":"Clinical and molecular characteristics of Korean patients with Kabuki syndrome","authors":"Ji-Hee Yoon, Soojin Hwang, Hyunwoo Bae, Dohyung Kim, Go Hun Seo, June-Young Koh, Young Seok Ju, Hyo-Sang Do, Soyoung Kim, Gu-Hwan Kim, Ja Hye Kim, Jin-Ho Choi, Beom Hee Lee","doi":"10.1038/s10038-024-01258-1","DOIUrl":"10.1038/s10038-024-01258-1","url":null,"abstract":"Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. The median age at clinical diagnosis was 18.5 months (IQR 7–58 months), and the median follow-up duration was 80.5 months (IQR 48–112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. This study enhances the understanding of the clinical and genetic characteristics of KS.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 9","pages":"417-423"},"PeriodicalIF":2.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186121","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}
Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.
{"title":"Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation","authors":"Takuya Morikawa, Shiroh Miura, Yusuke Uchiyama, Shigeyoshi Hiruki, Yinrui Sun, Ryuta Fujioka, Hiroki Shibata","doi":"10.1038/s10038-024-01260-7","DOIUrl":"10.1038/s10038-024-01260-7","url":null,"abstract":"Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 9","pages":"411-416"},"PeriodicalIF":2.6,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173477","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}
Human infertility affects 10–15% of couples. Asthenozoospermia accounts for 18% of men with infertility and is a common male infertility phenotype. The nexin-dynein regulatory complex (N-DRC) is a large protein complex in the sperm flagellum that connects adjacent doublets of microtubules. Defects in the N-DRC can disrupt cilia/flagellum movement, resulting in primary ciliary dyskinesia and male infertility. Using whole-exome sequencing, we identified a pathological homozygous variant of the dynein regulatory complex subunit 3 (DRC3) gene, which expresses leucine-rich repeat-containing protein 48, a component of the N-DRC, in a patient with asthenozoospermia. The variant ENST00000313838.12: c.644dup (p. Glu216GlyfsTer36) causes premature translational arrest of DRC3, resulting in a dysfunctional DRC3 protein. The patient’s semen count, color, and pH were normal according to the reference values of the World Health Organization guidelines; however, sperm motility and progressive motility were reduced. DRC3 protein was not detected in the patient’s sperm and the ultrastructure of the patient’s sperm flagella was destroyed. More importantly, the DRC3 variant reduced its interaction with other components of the N-DRC, including dynein regulatory complex subunits 1, 2, 4, 5, 7, and 8. Our data not only revealed the essential biological functions of DRC3 in sperm flagellum movement and structure but also provided a new basis for the clinical genetic diagnosis of male infertility.
{"title":"Homozygous variant in DRC3 (LRRC48) gene causes asthenozoospermia and male infertility","authors":"Jiao Qin, Jinyu Wang, Jianhai Chen, Jinyan Xu, Shanling Liu, Dong Deng, Fuping Li","doi":"10.1038/s10038-024-01253-6","DOIUrl":"10.1038/s10038-024-01253-6","url":null,"abstract":"Human infertility affects 10–15% of couples. Asthenozoospermia accounts for 18% of men with infertility and is a common male infertility phenotype. The nexin-dynein regulatory complex (N-DRC) is a large protein complex in the sperm flagellum that connects adjacent doublets of microtubules. Defects in the N-DRC can disrupt cilia/flagellum movement, resulting in primary ciliary dyskinesia and male infertility. Using whole-exome sequencing, we identified a pathological homozygous variant of the dynein regulatory complex subunit 3 (DRC3) gene, which expresses leucine-rich repeat-containing protein 48, a component of the N-DRC, in a patient with asthenozoospermia. The variant ENST00000313838.12: c.644dup (p. Glu216GlyfsTer36) causes premature translational arrest of DRC3, resulting in a dysfunctional DRC3 protein. The patient’s semen count, color, and pH were normal according to the reference values of the World Health Organization guidelines; however, sperm motility and progressive motility were reduced. DRC3 protein was not detected in the patient’s sperm and the ultrastructure of the patient’s sperm flagella was destroyed. More importantly, the DRC3 variant reduced its interaction with other components of the N-DRC, including dynein regulatory complex subunits 1, 2, 4, 5, 7, and 8. Our data not only revealed the essential biological functions of DRC3 in sperm flagellum movement and structure but also provided a new basis for the clinical genetic diagnosis of male infertility.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 8","pages":"401-409"},"PeriodicalIF":2.6,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071261","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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