Annals of Human Genetics最新文献

{"title":"A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness","authors":"Sanaz Mohammadi,&nbsp;Hossein Jafari Khamirani,&nbsp;Maryam Baneshi,&nbsp;Neda Kamal,&nbsp;Jamal Manoocheri,&nbsp;Mahsa Saffar,&nbsp;Mehdi Dianatpour,&nbsp;Seyed Mohammad Bagher Tabei,&nbsp;Seyed Alireza Dastgheib","doi":"10.1111/ahg.12501","DOIUrl":"10.1111/ahg.12501","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3>1.1 Introduction</h3>\u0000 \u0000 <p>Hereditary sensory neuropathy (HSN) describes as a heterogeneous group of peripheral neuropathies. HSN type 1 (HSN1) is one subtype characterized by distal sensory impairment that occurs in the form of numbness, tingling, or pain. To date, only two variants in the atlastin GTPase 3 (ATL3) gene have been identified that result in hereditary sensory neuropathy type 1F (HSN1F) with autosomal dominantinheritance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3>1.2 Methods</h3>\u0000 \u0000 <p>We sudied and examined who present with sensory disturbances and muscle weakness in their lower limb. Patients underwent Whole Exome Sequencing and Sanger sequencing was performed in families for validation of detected variant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3>1.3 Results</h3>\u0000 \u0000 <p>Here, we identified two Iranian families carrying the novel heterozygous stop variant NM_015459.5: c.16C&gt;T, p.Arg6Ter in <i>ATL3</i> that led to disturbed pain and touch sensitivity. This variant in the ATL3 gene was detected in both families (NM_015459.5: c.16C&gt;T, p.Arg6Ter) by whole-exome sequencing and confirmed by Sanger sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3>1.4 Conclusion</h3>\u0000 \u0000 <p>In this study, the subjects manifested weakness of distal limb muscles and numbness of the lower extremities. In addition, some unusual features, including hearing problems and inability to sit and walk presented in one of the patients. Eventually, we provide a case-based review of the clinical features associated with HSN1F. Hitherto, only 11 patients with HSN1F have been reported. We compared our findings to previously reported cases, suggesting that the clinical features are generally variable in the HSN1F patients.</p>\u0000 </section>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"147-157"},"PeriodicalIF":1.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10030893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of molecular diagnostic platform for α0-thalassemia 44.6 kb (Chiang Rai, --CR) deletion in individuals with microcytic red blood cells across Thailand","authors":"Pinyaphat Khamphikham,&nbsp;Oravee Hanmanoviriya,&nbsp;Somsakul Pop Wongpalee,&nbsp;Thongperm Munkongdee,&nbsp;Kittiphong Paiboonsukwong,&nbsp;Yupin Jopang,&nbsp;Chaowanee Wangchauy,&nbsp;Charan Sancharernsook,&nbsp;Nathawat Jinorose,&nbsp;Sakorn Pornprasert","doi":"10.1111/ahg.12496","DOIUrl":"https://doi.org/10.1111/ahg.12496","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The α⁰-thalassemia 44.6 kb or Chiang Rai (--^CR) deletion has been reported in northern Thailand and is capable of causing hemoglobin (Hb) H disease and a lethal α-thalassemia genotype, Hb Bart's hydrops fetalis, in this region. However, there are no current data regarding the frequency of --^CR nationwide due to a lack of effective diagnostic assay. Therefore, this study aimed to develop a reliable platform for simultaneous genotyping of --^CR and two common α⁰-thalassemias in Thailand (--^SEA and --^THAI) and investigate the frequency of --^CR across Thailand.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Multiplex gap-PCR assay and five renewable plasmid DNA controls for --^CR, --^SEA, --^THAI, α2-globin (<i>HBA2</i>), and β-actin (<i>ACTB</i>) were newly developed and validated with reference methods. The developed assay was further tested on 1046 unrelated individuals with a reduced mean corpuscular volume (MCV) of less than 75 fl for investigating genotypic and allelic spectrum of --^CR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our developed assay showed 100% concordance with reference methods. The results were valid and reproducible throughout hundreds of reactions. Comparison of the genotypic and allelic spectra revealed that heterozygous --^SEA (--^SEA/αα) and --^SEA alleles were dominant with the frequency of 22.85% (239/1046) and 13.34% (279/2092), respectively. Of these, --^THAI and --^CR were relatively rare in this population and comparable to each other with the allelic frequency of 0.14% (3/2092).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study successfully established a reliable molecular diagnostic platform for genotyping of --^CR, --^SEA, and --^THAI in a single reaction. Additionally, we demonstrated the frequency of --^CR in Thailand for the first time and provided knowledge basis for the planning of severe α-thalassemia prevention and control programs in Thailand, where thalassemia is endemic.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"137-145"},"PeriodicalIF":1.9,"publicationDate":"2023-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50124741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into gene tissue specificity and protein–protein interactions in the context of purifying selection in humans","authors":"Massimo Mezzavilla,&nbsp;Massimiliano Cocca","doi":"10.1111/ahg.12497","DOIUrl":"10.1111/ahg.12497","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>How much are natural selection and gene characteristics, such as the number of protein-protein interactions (PPIs), tissue specificity (𝞽), and expression level, connected?</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In order to investigate these relationships, we combined different metrics linked to genetic constraints and analyzed their distribution concerning PPIs, 𝞽 and expression levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We discovered a positive correlation between genetic constraints, PPIs, and expression levels in all tissues. On the other hand, we obtained a negative correlation between genetic constraints and 𝞽. Furthermore, the fraction of variance in PPI and 𝞽 explained by the constraints metrics is around 6% and 10%, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We observed that the variance of expression of tissue-specific genes seems not related to their level of selection constraints, which is the opposite of what is found on non-tissue-specific genes. Overall these observations would help to elucidate the relationship between natural selection and gene features.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"75-79"},"PeriodicalIF":1.9,"publicationDate":"2023-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9073379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimarker omnibus tests by leveraging individual marker summary statistics from large biobanks","authors":"Angela M. Zigarelli,&nbsp;Hanna M. Venera,&nbsp;Brody A. Receveur,&nbsp;Jack M. Wolf,&nbsp;Jason Westra,&nbsp;Nathan L. Tintle","doi":"10.1111/ahg.12495","DOIUrl":"10.1111/ahg.12495","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>As biobanks become increasingly popular, access to genotypic and phenotypic data continues to increase in the form of precomputed summary statistics (PCSS). Widespread accessibility of PCSS alleviates many issues related to biobank data, including that of data privacy and confidentiality, as well as high computational costs. However, questions remain about how to maximally leverage PCSS for downstream statistical analyses. Here we present a novel method for testing the association of an arbitrary number of single nucleotide variants (SNVs) on a linear combination of phenotypes after adjusting for covariates for common multimarker tests (e.g., SKAT, SKAT-O) without access to individual patient-level data (IPD). We validate exact formulas for each method, and demonstrate their accuracy through simulation studies and an application to fatty acid phenotypic data from the Framingham Heart Study.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"125-136"},"PeriodicalIF":1.9,"publicationDate":"2023-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9514791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity","authors":"Feyzanur Yildirimtepe Caldiran,&nbsp;Koksal Deveci,&nbsp;Ercan Cacan","doi":"10.1111/ahg.12493","DOIUrl":"10.1111/ahg.12493","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by variations in the <i>MEFV</i> gene, which encodes the pyrin protein, a member of the inflammasomes. Despite the complex pathogenesis of FMF, epigenetic changes also play roles in the disease progression. In our previous study, we observed a relationship between <i>NLRP13</i>, which is one of the members of the inflammasome complex and has a pyrin domain in its structure, and the <i>MEFV</i> gene using the STRING database. In this study, we examined <i>NLRP13</i> expression and methylation status in 40 patients with FMF attack and 20 healthy individuals. We then investigated the global DNA methylation status of patients with FMF in the attack period and control groups. We further examined the relationship between the clinical manifestation and global methylation as well as <i>NLRP13</i> gene expression of patients with FMF and healthy individuals. As a result, we showed that hypomethylation in patients with FMF leads to different clinical outcomes in terms of disease severity. In addition, the data indicated that <i>NLRP13</i> inflammasome is epigenetically controlled in patients with FMF and the presence of amyloidosis may affect the hypermethylation of this gene. Moreover, <i>NLRP13</i> was silenced because of the hypermethylation of the promoter. The increase of methylation level at the promoter region participated in the inactivation of <i>NLRP13</i>. In the current study, we not only found a new gene that plays a role in the pathogenesis of FMF disease, but also new evidence for the epigenetic regulation of the disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"115-124"},"PeriodicalIF":1.9,"publicationDate":"2022-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9514326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High diagnostic yield of targeted next-generation sequencing panel as a first-tier molecular test for the patients with myopathy or muscular dystrophy","authors":"Büşranur Çavdarlı,&nbsp;Özlem Yayici Köken,&nbsp;Saide Betül Arslan Satılmış,&nbsp;Şule Bilen,&nbsp;Didem Ardıçlı,&nbsp;Ahmet Cevdet Ceylan,&nbsp;Cavidan Nur Semerci Gündüz,&nbsp;Haluk Topaloğlu","doi":"10.1111/ahg.12492","DOIUrl":"10.1111/ahg.12492","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Muscular dystrophies are a heterogeneous group of neuromuscular disorders with a wide range of the clinical and genetic spectrum. Whole-exome sequencing (WES) has been on the rise to become the usual method of choice for molecular diagnosis in patients presenting with muscular dystrophy or congenital or metabolic myopathy phenotype. Here, we used a panel with 47 genes including not only muscular dystrophy but also myopathy-associated genes that had been used as a first-tier approach. A total of 146 patients who were referred to our clinic with the prediagnosis of muscular dystrophy and/or myopathy were included in the study. Dystrophin gene deletion/duplication was ruled out on the patients with a preliminary diagnosis of Duchenne muscular dystrophy. In this study, the molecular etiology of 67 patients was proved with the gene panel with a diagnostic yield of 46%. Causal variants were identified in 23 genes including <i>CAPN3(11)</i>, <i>DYSF(9)</i>, <i>DMD(8)</i>, <i>SGCA(5)</i>, <i>TTN(4)</i>, <i>LAMA2(3)</i>, <i>LMNA(3)</i>, <i>SGCB(3)</i>, <i>COL6A1(3)</i>, <i>DES (2)</i>, <i>CAV3(2)</i>, <i>FKRP(2)</i>, <i>FKTN(2)</i>, <i>ANO5</i>, <i>COL6A2</i>, <i>CLCN1</i>, <i>GNE</i>, <i>POMGNT1</i>, <i>POMGNT2</i>, <i>POMT2</i>, <i>SYNE1</i>, <i>TCAP</i>, and <i>FLNC</i> with 16 novel variants. There were 27 patients with uncertain molecular results including the ones who had a variant of uncertain significance, who had only one heterozygous variant for an autosomal recessive disease, and the ones who had two variants in different genes. Molecular diagnosis in muscular dystrophy is essential to plan clinical management and choosing treatment options. Also, the results will affect the reproduction options. Targeted next-generation sequencing is a cost-effective method that reduces the WES requirements with a significant diagnostic rate.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"104-114"},"PeriodicalIF":1.9,"publicationDate":"2022-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9565650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimation of genetic heritabilities of human traits in case–control studies","authors":"Die Hu,&nbsp;Shuyue Chen,&nbsp;Hong Zhang","doi":"10.1111/ahg.12491","DOIUrl":"10.1111/ahg.12491","url":null,"abstract":"It is of great interest to detect missing heritability for human complex traits. Additive genetic effects (ADD), maternal genetic effects (MGE), and parent‐of‐origin effects (POE) play important roles in genetic mechanisms. Methods have been developed in the literature to analyze heritabilities due to ADD, POE, and MGE separately but not simultaneously. In this paper, a new model termed APM is proposed based on mother–child duos genetic data, which orthogonally decomposes heritabilities due to ADD, POE, and MGE. This orthogonal decomposition is biologically interpretable since it ideally characterizes independent contributions due to the three effects. We focus on case–control data that are widely adopted in genetics studies and develop a novel method R‐PCGC by adjusting estimation biases due to sampling bias in case–control studies and imposing nonnegative constraints on the heritability estimates. Large sample properties such as consistency and asymptotic normality are established for R‐PCGC. The desired properties of R‐PCGC (i.e., asymptotic unbiasedness and nonnegativity) are confirmed through simulations. Finally, R‐PCGC regression is applied to a case–control study of preterm births from the Danish National Birth Cohort (DNBC).","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"91-103"},"PeriodicalIF":1.9,"publicationDate":"2022-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9513028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of key variants correlated with susceptibility of primary osteoporosis in the Chinese Han group","authors":"Yanjiao Li,&nbsp;Qi Liu,&nbsp;Qiuye Ma,&nbsp;Zhaoxia Ma,&nbsp;Juan Chen,&nbsp;An Yu,&nbsp;Changguo Ma,&nbsp;Lihua Qiu,&nbsp;Hong Shi,&nbsp;Hongsuo Liang,&nbsp;Min Hu","doi":"10.1111/ahg.12490","DOIUrl":"10.1111/ahg.12490","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Primary osteoporosis is a systemic skeletal disease characterized by reduced bone mass and vulnerability to fractures. The genetics of osteoporosis in the Chinese population remain unclear, which hinders the prevention and treatment of osteoporosis in China. This study aimed to explore the susceptibility genes and the roles played by their variants in osteoporosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples were collected from 45 osteoporosis patients and 30 healthy individuals, and genome-wide association study was performed on array data. The expression levels of the candidate gene in different genotypes were further determined by using quantitative real-time PCR. Moreover, the differentiation capacity of bone marrow mesenchymal stem cells under different genotypes from osteoporosis patients was investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The most significant variant rs1891632 located in the upstream (918 bp) region of <i>CRB2</i>, which could down-regulate the expression levels of <i>CRB2</i> in genotype-tissue expression database and played an essential role in the regulation of osteoblastic and osteoclastic differentiation during skeletal development. Another significant variant rs1061657 located within the 3′UTR region of <i>TBX3</i> gene. We found that the mRNA levels of <i>TBX3</i> decreased in the bMSCs of old osteoporosis patients. Interestingly, osteoblast differentiation capacity and <i>TBX3</i> mRNA levels were similar between the young healthy individuals carrying derived and ancestral allele of rs1061657, whereas the differentiation capacity and <i>TBX3</i> mRNA levels dramatically declined in elderly patients with osteoporosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The variant rs1061657 might affect the osteogenesis of bMSCs in an age-dependent manner and that <i>TBX3</i> may be a key susceptibility gene for primary osteoporosis. In conclusion, <i>CRB2</i> and <i>TBX3</i> may influence the development of osteoporosis; additionally, rs1891632 and rs1061657, as the key variants first reported to be associated with primary osteoporosis, may potentially contribute to predicting the risk of osteoporosis (especially for older individuals) and may serve as therapeutic targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"63-74"},"PeriodicalIF":1.9,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9129503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of next-generation sequencing in the examination of signaling genes in Brca1/2-negative breast cancer cases","authors":"Naci Cine,&nbsp;Cansu Ugurtas,&nbsp;Merve Gokbayrak,&nbsp;Duygu Aydin,&nbsp;Gulhan Demir,&nbsp;Seda Kuru,&nbsp;Deniz Sunnetci-Akkoyunlu,&nbsp;Seda Eren-Keskin,&nbsp;Turgay Simsek,&nbsp;Devrim Cabuk,&nbsp;Maksut Gorkem Aksu,&nbsp;Nuh Zafer Canturk,&nbsp;Hakan Savli","doi":"10.1111/ahg.12488","DOIUrl":"10.1111/ahg.12488","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Breast cancer is the most prevalent malignancy in women worldwide. Although pathogenic variants in the <i>BRCA1/2</i> genes are responsible for the majority of hereditary breast cancer cases, a substantial proportion of patients are negative for pathogenic variations in these genes. In cancers, the signal transduction pathways of the cell are usually affected first. Therefore, this study aimed to detect and classified genetic variations in non-<i>BRCA</i> signaling genes and investigate the underlying genetic causes of susceptibility to breast cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ninety-six patients without pathogenic variants in the <i>BRCA1/2</i> genes who met the inclusion criteria were enrolled in the study, and 34 genes were analyzed using next-generation sequencing (NGS) for genetic analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Based on the ClinVar database or American College of Medical Genetics criteria, a total of 55 variants of 16 genes were detected in 43 (44.8%) of the 96 patients included in the study. The pathogenic variants were found in the <i>TP53, CHEK2</i>, and <i>RET</i> genes, whereas the likely pathogenic variants were found in the <i>FGFR1, FGFR3, EGFR</i>, and <i>NOTCH1</i> genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The examination of signaling genes in patients who met the established criteria for hereditary breast cancer but were negative for <i>BRCA1/2</i> pathogenic variants provided additional information for approximately 8% of the families. The results of the present study suggest that NGS is a powerful tool for investigating the underlying genetic causes of occurrence and progression of breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"28-49"},"PeriodicalIF":1.9,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9129501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The expression of NOTUM in replantation of severed fingers may be an important treatment factor","authors":"Bin Li,&nbsp;Libing Xiao,&nbsp;Danhong Ye,&nbsp;Siyi Zhong,&nbsp;Qiaoyu Yan","doi":"10.1111/ahg.12487","DOIUrl":"10.1111/ahg.12487","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>After years of development, digital replantation has become a mature treatment. Although the <i>NOTUM</i> gene has been shown to be involved in the formation of vertebrate nerves, whether it contributes to the osteogenic mechanism of severed finger replantation remains unknown. In response to this, this study investigates the specific details of <i>NOTUM</i> involvement in replantation of severed fingers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The experimental subjects are patients with replantation of severed fingers from Shulan International Medical College of Shulan (Hangzhou) Hospital affiliated to Zhejiang Shuren University. In addition to using bone marrow mesenchymal stem cells (BMSCs) as an in vitro system, this experiment also involves quantitative polymerase chain reaction, microarray analysis, cell counting Kit-8, ethynyl deoxyuridine staining and Western blot analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The expression level of NOTUM in the severed finger replantation group is lower than that in the normal group. NOTUM inhibits cell growth and cell transfer, osteogenic differentiation and β-catenin gene expression in BMSCs. Luciferase reporter assay illustrated that β-catenin wild type closely correlated with NOTUM. The inhibition of β-catenin increases the effects of <i>NOTUM</i> on cell growth, cell transfer and osteogenic differentiation of BMSCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Considering that <i>NOTUM</i> can inhibit cell growth, cell transfer, osteogenic differentiation of BMSCs, as well as the gene expression of β-catenin, it may be a biomarker of osteogenic differentiation and a potential therapeutic target for replantation of severed fingers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"18-27"},"PeriodicalIF":1.9,"publicationDate":"2022-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10867517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}