Pub Date : 2024-03-07DOI: 10.1038/s10038-024-01240-x
Silvia Morlino, Lorenzo Vaccaro, Maria Pia Leone, Grazia Nardella, Luigi Bisceglia, Rocco Pio Ortore, Giannandrea Verzicco, Lazzaro Cassano, Marco Castori, Davide Cacchiarelli, Lucia Micale
Rare heterozygous variants in exons 33-34 of the SRCAP gene are associated with Floating-Harbor syndrome and have a dominant-negative mechanism of action. At variance, heterozygous null alleles falling in other parts of the same gene cause developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) syndrome. We report an 18-year-old man with DEHMBA syndrome and obstructive sleep apnea, who underwent exome sequencing (ES) and whole transcriptome sequencing (WTS) on peripheral blood. Trio analysis prioritized the de novo heterozygous c.5658+5 G > A variant. WTS promptly demostrated four different abnormal transcripts affecting >40% of the reads, three of which leading to a frameshift. This study demonstrated the efficacy of a combined ES-WTS approach in solving undiagnosed cases. We also speculated that sleep respiratory disorder may be an underdiagnosed complication of DEHMBA syndrome.
SRCAP 基因 33-34 号外显子中的罕见杂合变异与浮港综合征有关，其作用机制为显性阴性。不同的是，落在同一基因其他部分的杂合子空等位基因会导致发育迟缓、肌张力低下、肌肉骨骼缺陷和行为异常（DEHMBA）综合征。我们报告了一名患有 DEHMBA 综合征和阻塞性睡眠呼吸暂停的 18 岁男子，他接受了外周血外显子组测序（ES）和全转录组测序（WTS）。三组分析优先确定了新发杂合 c.5658+5 G > A 变异。WTS 迅速发现了四种不同的异常转录本，影响了 40% 以上的读数，其中三种导致了框移位。这项研究证明了 ES-WTS 联合方法在解决未确诊病例方面的有效性。我们还推测，睡眠呼吸障碍可能是 DEHMBA 综合征诊断不足的并发症。
{"title":"Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder","authors":"Silvia Morlino, Lorenzo Vaccaro, Maria Pia Leone, Grazia Nardella, Luigi Bisceglia, Rocco Pio Ortore, Giannandrea Verzicco, Lazzaro Cassano, Marco Castori, Davide Cacchiarelli, Lucia Micale","doi":"10.1038/s10038-024-01240-x","DOIUrl":"10.1038/s10038-024-01240-x","url":null,"abstract":"Rare heterozygous variants in exons 33-34 of the SRCAP gene are associated with Floating-Harbor syndrome and have a dominant-negative mechanism of action. At variance, heterozygous null alleles falling in other parts of the same gene cause developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) syndrome. We report an 18-year-old man with DEHMBA syndrome and obstructive sleep apnea, who underwent exome sequencing (ES) and whole transcriptome sequencing (WTS) on peripheral blood. Trio analysis prioritized the de novo heterozygous c.5658+5 G > A variant. WTS promptly demostrated four different abnormal transcripts affecting >40% of the reads, three of which leading to a frameshift. This study demonstrated the efficacy of a combined ES-WTS approach in solving undiagnosed cases. We also speculated that sleep respiratory disorder may be an underdiagnosed complication of DEHMBA syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"287-290"},"PeriodicalIF":3.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049674","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 association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes","authors":"Jialin Sun, Mujia Li, Huaqin Sun, Ziyuan Lin, Bing Shi, Zhonglin Jia","doi":"10.1038/s10038-024-01239-4","DOIUrl":"10.1038/s10038-024-01239-4","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"169-169"},"PeriodicalIF":3.5,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01239-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039578","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 : 2024-03-01DOI: 10.1038/s10038-024-01234-9
Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li, Jia-Feng Lin
Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett’s esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10−5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.
{"title":"Potential drug targets for gastroesophageal reflux disease and Barrett’s esophagus identified through Mendelian randomization analysis","authors":"Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li, Jia-Feng Lin","doi":"10.1038/s10038-024-01234-9","DOIUrl":"10.1038/s10038-024-01234-9","url":null,"abstract":"Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett’s esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10−5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"245-253"},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140001542","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 : 2024-02-29DOI: 10.1038/s10038-024-01231-y
Alok Sharma, Artem Lysenko, Shangru Jia, Keith A. Boroevich, Tatsuhiko Tsunoda
The field of omics, driven by advances in high-throughput sequencing, faces a data explosion. This abundance of data offers unprecedented opportunities for predictive modeling in precision medicine, but also presents formidable challenges in data analysis and interpretation. Traditional machine learning (ML) techniques have been partly successful in generating predictive models for omics analysis but exhibit limitations in handling potential relationships within the data for more accurate prediction. This review explores a revolutionary shift in predictive modeling through the application of deep learning (DL), specifically convolutional neural networks (CNNs). Using transformation methods such as DeepInsight, omics data with independent variables in tabular (table-like, including vector) form can be turned into image-like representations, enabling CNNs to capture latent features effectively. This approach not only enhances predictive power but also leverages transfer learning, reducing computational time, and improving performance. However, integrating CNNs in predictive omics data analysis is not without challenges, including issues related to model interpretability, data heterogeneity, and data size. Addressing these challenges requires a multidisciplinary approach, involving collaborations between ML experts, bioinformatics researchers, biologists, and medical doctors. This review illuminates these complexities and charts a course for future research to unlock the full predictive potential of CNNs in omics data analysis and related fields.
{"title":"Advances in AI and machine learning for predictive medicine","authors":"Alok Sharma, Artem Lysenko, Shangru Jia, Keith A. Boroevich, Tatsuhiko Tsunoda","doi":"10.1038/s10038-024-01231-y","DOIUrl":"10.1038/s10038-024-01231-y","url":null,"abstract":"The field of omics, driven by advances in high-throughput sequencing, faces a data explosion. This abundance of data offers unprecedented opportunities for predictive modeling in precision medicine, but also presents formidable challenges in data analysis and interpretation. Traditional machine learning (ML) techniques have been partly successful in generating predictive models for omics analysis but exhibit limitations in handling potential relationships within the data for more accurate prediction. This review explores a revolutionary shift in predictive modeling through the application of deep learning (DL), specifically convolutional neural networks (CNNs). Using transformation methods such as DeepInsight, omics data with independent variables in tabular (table-like, including vector) form can be turned into image-like representations, enabling CNNs to capture latent features effectively. This approach not only enhances predictive power but also leverages transfer learning, reducing computational time, and improving performance. However, integrating CNNs in predictive omics data analysis is not without challenges, including issues related to model interpretability, data heterogeneity, and data size. Addressing these challenges requires a multidisciplinary approach, involving collaborations between ML experts, bioinformatics researchers, biologists, and medical doctors. This review illuminates these complexities and charts a course for future research to unlock the full predictive potential of CNNs in omics data analysis and related fields.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"487-497"},"PeriodicalIF":2.6,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01231-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996432","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 : 2024-02-29DOI: 10.1038/s10038-024-01229-6
Paniz Farshadyeganeh, Takahiro Yamada, Hirofumi Ohashi, Gen Nishimura, Hiroki Fujita, Yuriko Oishi, Misa Nunode, Shuku Ishikawa, Jun Murotsuki, Yuri Yamashita, Shiro Ikegawa, Tomoo Ogi, Eri Arikawa-Hirasawa, Kinji Ohno
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman–Handmaker type (DDSH) and nonlethal Rolland–Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz–Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.
骨骼发育不良（DD）是一种严重的骨骼发育不良，包括两个亚型：致死型 Silverman-Handmaker 型（DDSH）和非致死型 Rolland-Desbuquois 型（DDRD）。DDSH是由编码perlecan的HSPG2的双偶性致病变体引起的，而DDRD的遗传原因仍未确定。Schwartz-Jampel 综合征（SJS）也是由 HSPG2 的双等位致病变体引起的，是 DDSH 的等位基因紊乱。在 SJS 和 DDSH 中，HSPG2 中分别有 44 个和 8 个致病变体。在此，我们报告了五名 DDRD 患者携带 HSPG2 中的四个致病变体：c.9970 G > A (p.G3324R)、c.559 C > T (p.R187X)、c7006 + 1 G > A 和 c.11562 + 2 T > G。单倍型分析显示，五名患者共有一个跨度为 85,973 bp 的创始单倍型。SJS、DDRD 和 DDSH 是具有 HSPG2 致病变体的等位基因疾病。
{"title":"Dyssegmental dysplasia Rolland–Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients","authors":"Paniz Farshadyeganeh, Takahiro Yamada, Hirofumi Ohashi, Gen Nishimura, Hiroki Fujita, Yuriko Oishi, Misa Nunode, Shuku Ishikawa, Jun Murotsuki, Yuri Yamashita, Shiro Ikegawa, Tomoo Ogi, Eri Arikawa-Hirasawa, Kinji Ohno","doi":"10.1038/s10038-024-01229-6","DOIUrl":"10.1038/s10038-024-01229-6","url":null,"abstract":"Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman–Handmaker type (DDSH) and nonlethal Rolland–Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz–Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"235-244"},"PeriodicalIF":3.5,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01229-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996433","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}
Psoriasis is a multifactorial genetic disorder manifested by hyperproliferation and abnormal differentiation of epidermal keratinocytes, along with the infiltration of inflammatory cells into the skin. Although ~80 genetic susceptibility variants were reported in psoriasis, many loci showed population-specific associations, warranting the need for more population-specific association studies in psoriasis. We determined the association of forty single nucleotide polymorphisms (SNPs) among 2136 psoriasis patients and normal individuals from eastern India. We investigated the expression of corresponding genes and evaluated the protein structure stability for the genes with susceptible coding variants. We found fifteen SNPs significantly associated with psoriasis, while additional three SNPs showed significant association when we classified the patients based on the presence of HLA-Cw6 allele. Epistatic interaction between HLA-Cw6 and other associated loci showed significant association with the SNPs at PSORS1 region, along with other five SNPs outside PSORS1. Three genes showed significant differential expression in psoriatic tissues compared to the adjacent normal skin tissues but were not differential when classified the patients based on their genotypes. SNP rs495337 at SPATA2 (Spermatogenesis Associated 2) showed a 1.2-fold increased risk among the HLA-Cw6 patients compared to combined samples. We found significant downregulation of SPATA2 among the patients with risk genotypes and HLA-Cw6 allele compared to the non-risk genotypes. Protein structure stability analysis showed reduced structural stability for all the mutant residues caused by the associated coding variants. Our study evaluated the genetic associations of psoriasis-susceptible variants in India and evaluated the possible functional significance of these associated variants in psoriasis.
{"title":"Identifying the genetic associations among the psoriasis patients in eastern India","authors":"Shantanab Das, Aditi Chandra, Anamika Das, Swapan Senapati, Gobinda Chatterjee, Raghunath Chatterjee","doi":"10.1038/s10038-024-01227-8","DOIUrl":"10.1038/s10038-024-01227-8","url":null,"abstract":"Psoriasis is a multifactorial genetic disorder manifested by hyperproliferation and abnormal differentiation of epidermal keratinocytes, along with the infiltration of inflammatory cells into the skin. Although ~80 genetic susceptibility variants were reported in psoriasis, many loci showed population-specific associations, warranting the need for more population-specific association studies in psoriasis. We determined the association of forty single nucleotide polymorphisms (SNPs) among 2136 psoriasis patients and normal individuals from eastern India. We investigated the expression of corresponding genes and evaluated the protein structure stability for the genes with susceptible coding variants. We found fifteen SNPs significantly associated with psoriasis, while additional three SNPs showed significant association when we classified the patients based on the presence of HLA-Cw6 allele. Epistatic interaction between HLA-Cw6 and other associated loci showed significant association with the SNPs at PSORS1 region, along with other five SNPs outside PSORS1. Three genes showed significant differential expression in psoriatic tissues compared to the adjacent normal skin tissues but were not differential when classified the patients based on their genotypes. SNP rs495337 at SPATA2 (Spermatogenesis Associated 2) showed a 1.2-fold increased risk among the HLA-Cw6 patients compared to combined samples. We found significant downregulation of SPATA2 among the patients with risk genotypes and HLA-Cw6 allele compared to the non-risk genotypes. Protein structure stability analysis showed reduced structural stability for all the mutant residues caused by the associated coding variants. Our study evaluated the genetic associations of psoriasis-susceptible variants in India and evaluated the possible functional significance of these associated variants in psoriasis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"205-213"},"PeriodicalIF":3.5,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972188","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 breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.
{"title":"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/s10038-024-01233-w","DOIUrl":"10.1038/s10038-024-01233-w","url":null,"abstract":"Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"225-230"},"PeriodicalIF":3.5,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972190","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}
Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.
{"title":"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/s10038-024-01225-w","DOIUrl":"10.1038/s10038-024-01225-w","url":null,"abstract":"Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"215-222"},"PeriodicalIF":3.5,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01225-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972189","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 : 2024-02-19DOI: 10.1038/s10038-024-01226-9
Emma Matthews, Ella F. Whittle, Faraan Khan, Meriel McEntagart, Christopher J. Carroll
Only five children with pathogenic PMPCB gene variants have been described and all carried missense variants. Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy. Three of the five died in childhood and none was older than age six when described. We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood. A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12.
{"title":"Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene","authors":"Emma Matthews, Ella F. Whittle, Faraan Khan, Meriel McEntagart, Christopher J. Carroll","doi":"10.1038/s10038-024-01226-9","DOIUrl":"10.1038/s10038-024-01226-9","url":null,"abstract":"Only five children with pathogenic PMPCB gene variants have been described and all carried missense variants. Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy. Three of the five died in childhood and none was older than age six when described. We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood. A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"283-285"},"PeriodicalIF":3.5,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01226-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905804","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}
CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.
{"title":"Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review","authors":"Xiao-Man Zhang, Kai-Li Xu, Jing-Hui Kong, Geng Dong, Shi-Jie Dong, Zhi-Xiao Yang, Shu-Jing Xu, Li Wang, Shu-Ying Luo, Yao-Dong Zhang, Chong-Chen Zhou, Wei-Yue Gu, Shi-Yue Mei","doi":"10.1038/s10038-024-01230-z","DOIUrl":"10.1038/s10038-024-01230-z","url":null,"abstract":"CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"197-203"},"PeriodicalIF":3.5,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905803","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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