Annals of Human Genetics最新文献

{"title":"The genetic era of childhood cancer: Identification of high-risk patients and germline sequencing approaches","authors":"Oscar Alonso-Luna,&nbsp;Gabriela E Mercado-Celis,&nbsp;Jorge Melendez-Zajgla,&nbsp;Marta Zapata-Tarres,&nbsp;Elvia Mendoza-Caamal","doi":"10.1111/ahg.12502","DOIUrl":"10.1111/ahg.12502","url":null,"abstract":"<p>Childhood cancer is a leading cause of death by disease in children ages 5–14, for which there are no preventive strategies. Due to early-age of diagnosis and short period of exposure to environmental factors, increasing evidence suggests childhood cancer could have strong association with germline alterations in predisposition cancer genes but, their frequency and distribution are largely unknown. Several efforts have been made to develop tools to identify children with increased risk of cancer who may benefit from genetic testing but their validation and application on a large scale is necessary. Research on genetic bases of childhood cancer is ongoing, in which several approaches for the identification of genetic variants related to cancer predisposition have been used. In this paper, we discuss the updated efforts, strategies, molecular mechanisms and clinical implications for germline predisposition gene alterations and the characterization of risk variants in childhood cancer.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 3","pages":"81-90"},"PeriodicalIF":1.9,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9566277","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":"Cover Image, Volume 87, Issue 1–2","authors":"","doi":"10.1111/ahg.12504","DOIUrl":"https://doi.org/10.1111/ahg.12504","url":null,"abstract":"<p><b>Cover Image</b>: The cover image is based on the Original Article <i>Proteome changes in autosomal recessive primary microcephaly</i> by Sami Zaqout et al., https://doi.org/10.1111/ahg.12489.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50118106","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":"","authors":"","doi":"10.1111/ahg.12485","DOIUrl":"10.1111/ahg.12485","url":null,"abstract":"<p>Retraction: Liu, H., Wang, T., Chen, X., Jiang, J., Song, N., Li, R., Xin, Y. and Xuan, S. (2020). Inhibition of miR-499-5p expression improves nonalcoholic fatty liver disease<i>. Annals of Human Genetics</i>. (https://doi.org/10.1111/ahg.12374).</p><p>The above article, published online on 20 January 2020 in Wiley Online Library (www.wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief Rosemary Ekong, the authors, and John Wiley &amp; Sons Ltd./University College London. The retraction has been agreed because there are inconsistencies in Figures 1 and 5 that render the data difficult to interpret and the original data could not be provided to support the conclusions. The authors asked to retract the manuscript because their confidence in the results has been undermined by these inconsistencies.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"80"},"PeriodicalIF":1.9,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117590/pdf/AHG-87-80.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9389046","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":"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}