Annals of Human Genetics最新文献

{"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}

{"title":"Proteome changes in autosomal recessive primary microcephaly","authors":"Sami Zaqout,&nbsp;Atef Mannaa,&nbsp;Oliver Klein,&nbsp;Angelika Krajewski,&nbsp;Joachim Klose,&nbsp;Lena Luise-Becker,&nbsp;Ahmed Elsabagh,&nbsp;Khaled Ferih,&nbsp;Nadine Kraemer,&nbsp;Ethiraj Ravindran,&nbsp;Konstantin Makridis,&nbsp;Angela M. Kaindl","doi":"10.1111/ahg.12489","DOIUrl":"10.1111/ahg.12489","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background/aim</h3>\u0000 \u0000 <p>: Autosomal recessive primary microcephaly (MCPH) is a rare and genetically heterogeneous group of disorders characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. MCPH3 is caused by biallelic variants in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene <i>CDK5RAP2</i>. In the corresponding <i>Cdk5rap2</i> mutant or Hertwig's anemia mouse model, congenital microcephaly as well as defects in the hematopoietic system, germ cells and eyes have been reported. The reduction in brain volume, particularly affecting gray matter, has been attributed mainly to disturbances in the proliferation and survival of early neuronal progenitors. In addition, defects in dendritic development and synaptogenesis exist that affect the excitation-inhibition balance. Here, we studied proteomic changes in cerebral cortices of <i>Cdk5rap2</i> mutant mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and methods</h3>\u0000 \u0000 <p>: We used large-gel two-dimensional gel (2-DE) electrophoresis to separate cortical proteins. 2-DE gels were visualized by a trained observer on a light box. Spot changes were considered with respect to presence/absence, quantitative variation and altered mobility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>: We identified a reduction in more than 30 proteins that play a role in processes such as cell cytoskeleton dynamics, cell cycle progression, ciliary functions and apoptosis. These proteome changes in the MCPH3 model can be associated with various functional and morphological alterations of the developing brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>: Our results shed light on potential protein candidates for the disease-associated phenotype reported in MCPH3.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"50-62"},"PeriodicalIF":1.9,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9129490","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":"High accuracy of single-molecule real-time sequencing in detecting a rare α-globin fusion gene in carrier screening population","authors":"Qiao-Miao Zhou,&nbsp;Fan Jiang,&nbsp;Jing Xu,&nbsp;Dan Lin,&nbsp;Ren-Liang Huang,&nbsp;Jian-Ying Zhou,&nbsp;Yan-Xia Qu,&nbsp;Dong-Zhi Li","doi":"10.1111/ahg.12486","DOIUrl":"10.1111/ahg.12486","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The α-globin fusion gene between the <i>HBA2</i> and <i>HBAP1</i> genes becomes clinically important in thalassemia screening because this fusion gene can cause severe hemoglobin (Hb) H disease when combining with α⁰-thalassemia (α⁰-thal). Due to its uncommon rearrangement in the α gene cluster without dosage changes, this fusion gene is undetectable by common molecular testing approaches used for α-thal diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we used the single-molecule real-time (SMRT) sequencing technique to detect this fusion gene in 23 carriers identified by next-generation sequencing (NGS) among 16,504 screened individuals. Five primers for α and β thalassemia were utilized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>According to the NGS results, the 23 carriers include 14 pure heterozygotes, eight compound heterozygotes with common α-thal alleles, and one homozygote. By using SMRT, the fusion mutant was successfully detected in all 23 carriers. Furthermore, SMRT corrected the diagnosis in two “pure” heterozygotes: one was compound heterozygote with anti-3.7 triplication, and the other was homozygote.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results indicate that SMRT is a superior method compared to NGS in detecting the α fusion gene, attributing to its efficient, accurate, and one-step <i>properties</i>.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"9-17"},"PeriodicalIF":1.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9080963","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":"Segregation analysis identifies specific alpha-defensin (DEFA1A3) SNP–CNV haplotypes in predisposition to IgA nephropathy","authors":"Nzar A. A. Shwan,&nbsp;Eric C. Moise,&nbsp;Paula E. Necsoiu,&nbsp;Amy J. Farr,&nbsp;Daniel P. Gale,&nbsp;Jonathan Barratt,&nbsp;John A. L. Armour","doi":"10.1111/ahg.12481","DOIUrl":"10.1111/ahg.12481","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immunoglobulin A (IgA) nephropathy is a disorder of the immune system affecting kidney function, and genome-wide association studies (GWAS) have defined numerous loci with associated variation, all implicating components of innate or adaptive immunity. Among these, single nucleotide polymorphisms (SNPs) in a region including the multiallelic copy number variation (CNV) of <i>DEFA1A3</i> are associated with IgA nephropathy in both European and Asian populations. At present, the precise factors underlying the observed associations at <i>DEFA1A3</i> have not been defined, although the key alleles differ between Asian and European populations, and multiple independent factors may be involved even within a single population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we measured <i>DEFA1A3</i> copy number in UK family trios with an offspring affected by IgA nephropathy, used the population distributions of joint SNP–CNV haplotypes to infer the likely segregation in trios, and applied transmission disequilibrium tests (TDT) to examine joint SNP–CNV haplotypes for over- or undertransmission into affected offspring from heterozygous parents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusions</h3>\u0000 \u0000 <p>We observed overtransmission of 3-copy class 2 haplotypes (raw <i>p</i> = 0.029) and some evidence for under-transmission of 3-copy class 1 haplotypes (raw <i>p</i> = 0.051), although these apparent effects were not statistically significant after correction for testing of multiple haplotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"1-8"},"PeriodicalIF":1.9,"publicationDate":"2022-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9422881","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":"Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study","authors":"Asma-Lamia Boumehdi,&nbsp;Farid Cherbal,&nbsp;Feriel Khider,&nbsp;Mohammed Oukkal,&nbsp;Hassen Mahfouf,&nbsp;Ferhat Zebboudj,&nbsp;Mustapha Maaoui","doi":"10.1111/ahg.12482","DOIUrl":"10.1111/ahg.12482","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: <i>MLH1</i> (exons 1, 9, 10, 13, 16), <i>MSH2</i> (exons 5, 6, 7, 12), <i>MSH6</i> (exons 4 and 8) and <i>PMS2</i> (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 <i>MLH1</i>, 2 <i>MSH2</i> and 1 <i>MSH6</i>). Of index cases and relatives who underwent genetic testing (<i>n</i> = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in <i>MLH1</i> (2) and one germline likely pathogenic variant in <i>MSH6</i> (1) never published in individuals with LS have been detected in the present study. The recurrent <i>MLH1</i> germline pathogenic variant c.1546C&gt;T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common <i>MSH2</i> germline pathogenic variant c.942+3A&gt;T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"328-352"},"PeriodicalIF":1.9,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33449476","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":"Study of variants in genes implicated in rare familial migraine syndromes and their association with migraine in 200,000 exome-sequenced UK Biobank participants","authors":"Katherine Alexis Markel,&nbsp;David Curtis","doi":"10.1111/ahg.12484","DOIUrl":"10.1111/ahg.12484","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Among exome-sequenced participants in the UK Biobank, we identified 7194 migraine cases with the remaining 193,433 participants classified as controls. We investigated rare variants in 10 genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene- and variant-based tests for association.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in <i>KCNK18</i>, p.(Phe139Trpfs*24), which had been shown to segregate with migraine with aura in a multiply affected pedigree, was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (<i>χ</i>² = 0.96, 1 df, <i>p</i> = 0.33).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Since there is no other reported evidence to implicate <i>KCNK18</i>, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"353-360"},"PeriodicalIF":1.9,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9915015","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}