Pub Date : 2024-04-02DOI: 10.1038/s10038-024-01248-3
Lin Wang, Shuji Mizumoto, Ruixue Zhang, Yuqi Zhang, Yuan Liu, Wenjing Cheng, Xin Li, Min Dan, Chunyan Zhang, Xinru Gao, Juan Wang, Jiaqi Han, Lianying Jiao, Yating Wang, Qiujie Jin, Lihui Yang, Chenxing Li, Shuxian Li, Jinhui Zhu, Hai Jiang, Gen Nishimura, Takahiro Yamada, Shuhei Yamada, Na Cai, Rong Qiang, Long Guo
Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.
{"title":"Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review","authors":"Lin Wang, Shuji Mizumoto, Ruixue Zhang, Yuqi Zhang, Yuan Liu, Wenjing Cheng, Xin Li, Min Dan, Chunyan Zhang, Xinru Gao, Juan Wang, Jiaqi Han, Lianying Jiao, Yating Wang, Qiujie Jin, Lihui Yang, Chenxing Li, Shuxian Li, Jinhui Zhu, Hai Jiang, Gen Nishimura, Takahiro Yamada, Shuhei Yamada, Na Cai, Rong Qiang, Long Guo","doi":"10.1038/s10038-024-01248-3","DOIUrl":"10.1038/s10038-024-01248-3","url":null,"abstract":"Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"321-327"},"PeriodicalIF":2.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140590573","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}
{"title":"Correction: Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population","authors":"Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi","doi":"10.1038/s10038-024-01245-6","DOIUrl":"10.1038/s10038-024-01245-6","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"185-185"},"PeriodicalIF":3.5,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01245-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318473","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 : 2024-03-25DOI: 10.1038/s10038-024-01232-x
Zihan Dong, Hongyu Zhao, Andrew T. DeWan
Identification of pleiotropy at the single nucleotide polymorphism (SNP) level provides valuable insights into shared genetic signals among phenotypes. One approach to study these signals is through mediation analysis, which dissects the total effect of a SNP on the outcome into a direct effect and an indirect effect through a mediator. However, estimated effects from mediation analysis can be confounded by the genetic correlation between phenotypes, leading to inaccurate results. To address this confounding effect in the context of genetic mediation analysis, we propose a restricted-maximum-likelihood (REML)-based mediation analysis framework called REML-mediation, which can be applied to either individual-level or summary statistics data. Simulations demonstrated that REML-mediation provides unbiased estimates of the true cross-trait causal effect, assuming certain assumptions, albeit with a slightly inflated standard error compared to traditional linear regression. To validate the effectiveness of REML-mediation, we applied it to UK Biobank data and analyzed several mediator-outcome trait pairs along with their corresponding sets of pleiotropic SNPs. REML-mediation successfully identified and corrected for genetic confounding effects in these trait pairs, with correction magnitudes ranging from 7% to 39%. These findings highlight the presence of genetic confounding effects in cross-trait epidemiological studies and underscore the importance of accounting for them in data analysis.
{"title":"A mediation analysis framework based on variance component to remove genetic confounding effect","authors":"Zihan Dong, Hongyu Zhao, Andrew T. DeWan","doi":"10.1038/s10038-024-01232-x","DOIUrl":"10.1038/s10038-024-01232-x","url":null,"abstract":"Identification of pleiotropy at the single nucleotide polymorphism (SNP) level provides valuable insights into shared genetic signals among phenotypes. One approach to study these signals is through mediation analysis, which dissects the total effect of a SNP on the outcome into a direct effect and an indirect effect through a mediator. However, estimated effects from mediation analysis can be confounded by the genetic correlation between phenotypes, leading to inaccurate results. To address this confounding effect in the context of genetic mediation analysis, we propose a restricted-maximum-likelihood (REML)-based mediation analysis framework called REML-mediation, which can be applied to either individual-level or summary statistics data. Simulations demonstrated that REML-mediation provides unbiased estimates of the true cross-trait causal effect, assuming certain assumptions, albeit with a slightly inflated standard error compared to traditional linear regression. To validate the effectiveness of REML-mediation, we applied it to UK Biobank data and analyzed several mediator-outcome trait pairs along with their corresponding sets of pleiotropic SNPs. REML-mediation successfully identified and corrected for genetic confounding effects in these trait pairs, with correction magnitudes ranging from 7% to 39%. These findings highlight the presence of genetic confounding effects in cross-trait epidemiological studies and underscore the importance of accounting for them in data analysis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"301-309"},"PeriodicalIF":2.6,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288307","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 : 2024-03-25DOI: 10.1038/s10038-024-01243-8
Yuying Wu, Weiling Chen, Yang Zhao, Minqi Gu, Yajuan Gao, Yamin Ke, Longkang Wang, Mengmeng Wang, Wenkai Zhang, Yaobing Chen, Weifeng Huo, Xueru Fu, Xi Li, Dongdong Zhang, Pei Qin, Fulan Hu, Yu Liu, Xizhuo Sun, Ming Zhang, Dongsheng Hu
Our study aimed to investigate the association between the transition of the TXNIP gene methylation level and the risk of incident type 2 diabetes mellitus (T2DM). This study included 263 incident cases of T2DM and 263 matched non-T2DM participants. According to the methylation levels of five loci (CpG1–5; chr1:145441102-145442001) on the TXNIP gene, the participants were classified into four transition groups: maintained low, low to high, high to low, and maintained high methylation levels. Compared with individuals whose methylation level of CpG2–5 at the TXNIP gene was maintained low, individuals with maintained high methylation levels showed a 61–87% reduction in T2DM risk (66% for CpG2 [OR: 0.34, 95% CI: 0.14, 0.80]; 77% for CpG3 [OR: 0.23, 95% CI: 0.07, 0.78]; 87% for CpG4 [OR: 0.13, 95% CI: 0.03, 0.56]; and 61% for CpG5 [OR: 0.39, 95% CI: 0.16, 0.92]). Maintained high methylation levels of four loci of the TXNIP gene are associated with a reduction of T2DM incident risk in the current study. Our study suggests that preserving hypermethylation levels of the TXNIP gene may hold promise as a potential preventive measure against the onset of T2DM.
{"title":"Visit to visit transition in TXNIP gene methylation and the risk of type 2 diabetes mellitus: a nested case-control study","authors":"Yuying Wu, Weiling Chen, Yang Zhao, Minqi Gu, Yajuan Gao, Yamin Ke, Longkang Wang, Mengmeng Wang, Wenkai Zhang, Yaobing Chen, Weifeng Huo, Xueru Fu, Xi Li, Dongdong Zhang, Pei Qin, Fulan Hu, Yu Liu, Xizhuo Sun, Ming Zhang, Dongsheng Hu","doi":"10.1038/s10038-024-01243-8","DOIUrl":"10.1038/s10038-024-01243-8","url":null,"abstract":"Our study aimed to investigate the association between the transition of the TXNIP gene methylation level and the risk of incident type 2 diabetes mellitus (T2DM). This study included 263 incident cases of T2DM and 263 matched non-T2DM participants. According to the methylation levels of five loci (CpG1–5; chr1:145441102-145442001) on the TXNIP gene, the participants were classified into four transition groups: maintained low, low to high, high to low, and maintained high methylation levels. Compared with individuals whose methylation level of CpG2–5 at the TXNIP gene was maintained low, individuals with maintained high methylation levels showed a 61–87% reduction in T2DM risk (66% for CpG2 [OR: 0.34, 95% CI: 0.14, 0.80]; 77% for CpG3 [OR: 0.23, 95% CI: 0.07, 0.78]; 87% for CpG4 [OR: 0.13, 95% CI: 0.03, 0.56]; and 61% for CpG5 [OR: 0.39, 95% CI: 0.16, 0.92]). Maintained high methylation levels of four loci of the TXNIP gene are associated with a reduction of T2DM incident risk in the current study. Our study suggests that preserving hypermethylation levels of the TXNIP gene may hold promise as a potential preventive measure against the onset of T2DM.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"311-319"},"PeriodicalIF":2.6,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288328","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}
{"title":"Correction: The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population","authors":"Masashi Idogawa, Tasuku Mariya, Yumi Tanaka, Tsuyoshi Saito, Hiroshi Nakase, Takashi Tokino, Akihiro Sakurai","doi":"10.1038/s10038-024-01241-w","DOIUrl":"10.1038/s10038-024-01241-w","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"231-234"},"PeriodicalIF":3.5,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01241-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119788","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}
Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism.
智障（ID）和自闭症谱系障碍（ASD）的病因多种多样，包括环境和遗传因素。我们的研究报告采用全外显子组测序（WES）技术，对一个近亲家庭中患有智障和自闭症谱系障碍的两个兄弟姐妹进行了精神科临床调查和分子分析。研究还进行了生物信息学预测和分子对接分析。这两名患者被诊断为深度智障、大脑皮质萎缩等脑部畸形、后天性小头畸形和自闭症三级。神经和神经精神检查显示，P2 的病情比 P1 更为严重，因为他无法行走，表现出畸形特征，并有自我和异性攻击行为。分子研究发现，这对兄妹中存在一种新型 TRAPPC9 双重无义突变（c.2920 C > T, p.R974X）。病情较重的患者（P2）在出现 TRAPPC9 变异的同时，还出现了 MID2 基因中的一个新的错义突变 c.166 C > T (p.R56C)，且为半合子状态，而他的姐姐 P1 只是携带者。三维建模和分子对接分析表明，c.166 C > T 变异可能影响 MID2 与 Astrin 的结合能力，导致微管动力学失调，引起大脑形态异常。据我们所知，MID2 基因突变（p.R56C）是首次在突尼斯检测到的基因突变，它导致了兄弟姐妹之间的表型差异。我们扩展了 TRAPPC9 和 MID2 突变的遗传和临床谱系，并强调了 X 连锁遗传和常染色体隐性遗传可能同时存在，从而导致 ID、小头畸形和自闭症。
{"title":"Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies","authors":"Marwa Kharrat, Chahnez Triki, Abir ben isaa, Wafa Bouchaala, Olfa Alila, Jihen Chouchen, Yosra Ghouliya, Fatma Kamoun, Abdelaziz Tlili, Faiza Fakhfakh","doi":"10.1038/s10038-024-01242-9","DOIUrl":"10.1038/s10038-024-01242-9","url":null,"abstract":"Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"291-299"},"PeriodicalIF":2.6,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101731","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 : 2024-03-08DOI: 10.1038/s10038-024-01236-7
Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid
Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.
MADD的双倍拷贝致病变异会导致一种非常罕见的神经发育障碍，其表型具有多重性，从严重的新生儿肌张力低下、发育不良、多器官功能障碍和早期致死，到表型相似但病情较轻且存活率较高。在本文中，我们报告了来自3个无血缘关系的埃及家庭的5名患者，其中4名患者表现为重度，表现为新生儿呼吸窘迫、肌张力低下和慢性腹泻，1名患者表现为轻度，表现为中度智力障碍和肌病。此外，我们还在所有患者中观察到远端关节畸形和非特异性脑结构异常。有趣的是，其中一名患者出现了小脑和脑干发育不全。全外显子组测序在 MADD 基因中发现了三个新的同源变异：两个可能致病的变异 [c.4321delC p.(Gln1441ArgfsTer46) 和 c.2620 C > T p.(Arg874Ter)] 以及一个意义不明的变异（c.4307 G > A, p.Arg1436Gln）。这些变异与所有家族成员的疾病都有分离。我们的研究结果证实，关节畸形、生殖器、心脏和脑结构异常是 MADD 的表现形式，扩大了 MADD 相关神经发育障碍的范围。此外，这些研究还进一步突显了 MADD 变异在不同器官系统中的汇聚导致了复杂的表型。
{"title":"New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder","authors":"Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid","doi":"10.1038/s10038-024-01236-7","DOIUrl":"10.1038/s10038-024-01236-7","url":null,"abstract":"Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"263-270"},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01236-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065255","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}
Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.
{"title":"A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases","authors":"Jessica Zucco, Federica Baldan, Lorenzo Allegri, Elisa Bregant, Nadia Passon, Alessandra Franzoni, Angela Valentina D’Elia, Flavio Faletra, Giuseppe Damante, Catia Mio","doi":"10.1038/s10038-024-01237-6","DOIUrl":"10.1038/s10038-024-01237-6","url":null,"abstract":"Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"271-282"},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01237-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065297","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}
{"title":"Correction: The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease","authors":"Tadashi Inoue, Ryuta Takase, Keiko Uchida, Kazuki Kodo, Kenji Suda, Yoriko Watanabe, Koh-Ichiro Yoshiura, Masaya Kunimatsu, Reina Ishizaki, Kenko Azuma, Kei Inai, Jun Muneuchi, Yoshiyuki Furutani, Hiroyuki Akagawa, Hiroyuki Yamagishi","doi":"10.1038/s10038-024-01238-5","DOIUrl":"10.1038/s10038-024-01238-5","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"223-223"},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01238-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065298","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 : 2024-03-07DOI: 10.1038/s10038-024-01235-8
David Curtis
A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.
{"title":"Weighted burden analysis of rare coding variants in 470,000 exome-sequenced UK Biobank participants characterises effects on hyperlipidaemia risk","authors":"David Curtis","doi":"10.1038/s10038-024-01235-8","DOIUrl":"10.1038/s10038-024-01235-8","url":null,"abstract":"A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"255-262"},"PeriodicalIF":3.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01235-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059587","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}
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