Annals of Human Genetics最新文献

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Incorporating familial risk, lifestyle factors, and pharmacogenomic insights into personalized noncommunicable disease (NCD) reports for healthcare funder beneficiaries participating in the Open Genome Project. 将家族风险、生活方式因素和药物基因组学见解纳入针对参与开放基因组计划的医疗保健资助受益人的个性化非传染性疾病 (NCD) 报告。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-10-29 DOI: 10.1111/ahg.12582
Manie De Klerk, Nicole Van Der Merwe, Johny Erasmus, Lindiwe Whati, Kelebogile E Moremi, Daniel W Olivier, Maritha J Kotze
{"title":"Incorporating familial risk, lifestyle factors, and pharmacogenomic insights into personalized noncommunicable disease (NCD) reports for healthcare funder beneficiaries participating in the Open Genome Project.","authors":"Manie De Klerk, Nicole Van Der Merwe, Johny Erasmus, Lindiwe Whati, Kelebogile E Moremi, Daniel W Olivier, Maritha J Kotze","doi":"10.1111/ahg.12582","DOIUrl":"10.1111/ahg.12582","url":null,"abstract":"<p><strong>Introduction: </strong>An ethics-guided decision-making framework was developed for applying pathology-supported genetic testing, a multifaceted pharmacodiagnostic approach that translates population risk stratification into clinical utility. We introduce this service, supported by the Open Genome Project, which aligns with the beneficence principle in personalized medicine.</p><p><strong>Methods: </strong>Genetic testing of six noncommunicable disease pathways was conducted as part of a pilot program, benchmarked against a readiness checklist for implementation of genomic medicine in Africa. Patient referral criteria were determined using healthcare funder claims data, employing the Adjusted Clinical Groupers and Resource Utilization Band risk rating structure to identify potential nonresponders to treatment.</p><p><strong>Results: </strong>Three of the 135 doctors (2.2%) invited expressed immediate disinterest in the pilot, while 24 (17.8%) actively participated. Inherited, lifestyle-triggered, and therapy-related pathologies were simultaneously assessed in case reports, with special medical scheme reimbursement tariff codes applied to 25 patient referrals. The findings were used by the participating genetic counselor to select three patients for whole exome sequencing, utilizing a novel, level-up data processing algorithm for adaptive reporting.</p><p><strong>Conclusion: </strong>This study demonstrated the implementation of genomics into an evolving workflow for patients with a history of frequent clinic visits. Eliminating the cost barrier provided valuable insights to guide future reimbursement policy decisions.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520809","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}
引用次数: 0
Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering. 对一个南印度近亲结婚大家庭进行的遗传分析揭示了 NAGPA 和四个迄今未报道的发育性口吃基因的新型变异。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-10-09 DOI: 10.1111/ahg.12579
G Nandhini Devi, Navneesh Yadav, Chandru Jayashankaran, Jeffrey Justin Margret, Mathuravalli Krishnamoorthy, Sorna Lakshmi A, Chandralekha Meenakshi Sundaram, N P Karthikeyan, B K Thelma, C R Srikumari Srisailapathy
{"title":"Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering.","authors":"G Nandhini Devi, Navneesh Yadav, Chandru Jayashankaran, Jeffrey Justin Margret, Mathuravalli Krishnamoorthy, Sorna Lakshmi A, Chandralekha Meenakshi Sundaram, N P Karthikeyan, B K Thelma, C R Srikumari Srisailapathy","doi":"10.1111/ahg.12579","DOIUrl":"https://doi.org/10.1111/ahg.12579","url":null,"abstract":"<p><strong>Background: </strong>Developmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in GNPTAB, GNPTG, and NAGPA involved in lysosomal pathway and AP4E1, IFNAR1, and ARMC3-signaling genes reported till date explain only ∼2.1% - 3.7% of persistent stuttering cases.</p><p><strong>Aim: </strong>We aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (n = 27) and further validation on additional extended family members (n = 21).</p><p><strong>Materials & methods: </strong>We employed hypothesis-free and pathway-based analyses.</p><p><strong>Results: </strong>A novel heterozygous exonic variant NM_016256.4:c.322G > A in NAGPA with reduced penetrance and predicted pathogenicity segregated with the phenotype in a large subset of the family. Reanalysis to identify additional disease-causing variant(s) revealed exonic heterozygous variants each in RIMS2 and XYLT1 in severely affected members; and IGF2R variant in a small subset of the family. Furthermore, pathway-based analysis uncovered NM_022089.4:c.3529G > A in ATP13A2 (PARK9) in affected members; and variants in GNPTAB and GNPTG of minor significance in a few affected members.</p><p><strong>Discussion: </strong>Genotype-phenotype correlation efforts suggest that the combined effect of gene variants at multiple loci or variants in a single gene in different subsets of the pedigree (genetic heterogeneity) may be contributing to stuttering in this family. More importantly, variants identified in ATP13A2, a Parkinson's disease gene also implicated in lysosomal dysfunction, and RIMS2 suggests for the first time a likely role of dopamine signaling in stuttering.</p><p><strong>Conclusion: </strong>Screening for these variants in independent stuttering cohorts would be astute.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387467","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}
引用次数: 0
DYNC2H1 splicing variants causing severe prenatal short-rib polydactyly syndrome and postnatal orofaciodigital syndrome. DYNC2H1剪接变体导致严重的产前短肋多趾综合征和产后无趾综合征。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-10-03 DOI: 10.1111/ahg.12581
Alice Porto Vasconcelos, Sofia Quental, João Parente Freixo, João Machado Pacheco, Sofia Rodrigues, Magda Magalhães, Renata Oliveira, Ana Costa Braga, Rita Quental
{"title":"DYNC2H1 splicing variants causing severe prenatal short-rib polydactyly syndrome and postnatal orofaciodigital syndrome.","authors":"Alice Porto Vasconcelos, Sofia Quental, João Parente Freixo, João Machado Pacheco, Sofia Rodrigues, Magda Magalhães, Renata Oliveira, Ana Costa Braga, Rita Quental","doi":"10.1111/ahg.12581","DOIUrl":"https://doi.org/10.1111/ahg.12581","url":null,"abstract":"<p><p>The DYNC2H1 gene has been associated with short-rib polydactyly syndrome (SRPS), among other skeletal ciliopathies. Two cases are presented of distinctive phenotypes resulting from splicing variants in DYNC2H1. The first is a 14-week-old fetus with enlarged nuchal translucency, oral hamartoma, malformed uvula, bifid epiglottis, short ribs, micromelia, long bone agenesis, polysyndactyly, heart defect, pancreatic cysts, multicystic dysplastic kidney, megabladder and trident acetabulum. A ciliopathies NGS panel revealed two compound heterozygous variants in DYNC2H1: c.7840-18T>G r.7841_7964del p.Gly2614Aspfs*5 and c.11070G>A r.11044_11116del p.Ile3682Aspfs*2. Both variants were initially classified as variants of uncertain significance but were reclassified as likely pathogenic after PCR-based RNA testing. The second is an 11-year-old overweight male with multiple accessory oral frenula, median cleft lip and alveolar ridge, polysyndactyly, brachydactyly, normal rib length, and hypogonadism. Exome sequencing revealed two compound heterozygous variants in DYNC2H1: c.6315del p.(Thr2106Glnfs*7), classified as likely pathogenic, and c.3303-16A>G p.(?), classified as a variant of uncertain significance. PCR-based RNA testing suggested that c.3303-16A>G induces an in-frame deletion: r.3303_3458del p.Asp1102_Arg1153del, although the normal transcript is still produced. These results are consistent with both SRPS type I/III in the first case and orofaciodigital syndrome in the second, an unprecedented description. This work thus improves the clinical and molecular knowledge of the phenotypes associated with splicing variants in the DYNC2H1 gene.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364164","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}
引用次数: 0
Traces of Bronze Age globalization in East Asia: Insights from a revised phylogeography of the Y-chromosome haplogroup Q1a1a-M120. 东亚青铜时代全球化的痕迹:从修订的 Y 染色体单倍群 Q1a1a-M120 系统地理学中获得的启示。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-09-25 DOI: 10.1111/ahg.12580
La-Su Mai, Xian-Peng Zhang, Kai-Jun Liu, Peng-Cheng Ma, Hui Li, Jin Sun, Lan-Hai Wei
{"title":"Traces of Bronze Age globalization in East Asia: Insights from a revised phylogeography of the Y-chromosome haplogroup Q1a1a-M120.","authors":"La-Su Mai, Xian-Peng Zhang, Kai-Jun Liu, Peng-Cheng Ma, Hui Li, Jin Sun, Lan-Hai Wei","doi":"10.1111/ahg.12580","DOIUrl":"https://doi.org/10.1111/ahg.12580","url":null,"abstract":"<p><strong>Objective: </strong>In this study, we aim to explore the genetic imprint of Bronze Age globalization in East Asia from a phylogeographic perspective by examining the Y-chromosome haplogroup Q1a1a-M120, and to identify key demographic processes involved in the formation of early China and the ancient Huaxia people.</p><p><strong>Methods: </strong>Over the past few decades, we have collected the sequences of 347 Y chromosomes from the haplogroup Q1a1a-M120. These sequences were utilized to analyze and reconstruct a highly revised phylogenetic tree with age estimates. And we analyzed the geographical distribution and spatial autocorrelation of nine major sub-branches of Q1a1a-M120. Finally, we observed the expansion of Q1a1a-M120 from the beginning of the Bronze Age in East Asia, along with the continuous dissemination of its sub-lineages among East Asian populations.</p><p><strong>Results: </strong>We suggest that certain sub-lineages played a significant role in the formation of states and early civilizations in China, as well as in the development of the ancient Huaxia people, who are the direct ancestors of the Han population. Overall, we propose that haplogroup Q-M120 played a role in the introduction of Bronze Age culture to the central region of East Asia. Therefore, it is haplogroup Q-M120, rather than the Western Eurasian paternal lineage, that expanded and contributed to the gene pool of the East Asian population.</p><p><strong>Conclusion: </strong>In summary, the globalization of the Bronze Age led to large-scale population replacement and admixture across various regions of Eurasia; our findings highlight the unique demographic processes that occurred in East Asia during this period.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339930","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}
引用次数: 0
Heritability and genetic correlations of obesity indices and cardiometabolic traits in the Northern Chinese families. 中国北方家庭肥胖指数和心脏代谢特征的遗传性和遗传相关性。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-09-06 DOI: 10.1111/ahg.12578
Binbin Lin, Li Pan, Huijing He, Yaoda Hu, Ji Tu, Ling Zhang, Ze Cui, Xiaolan Ren, Xianghua Wang, Jing Nai, Guangliang Shan
{"title":"Heritability and genetic correlations of obesity indices and cardiometabolic traits in the Northern Chinese families.","authors":"Binbin Lin, Li Pan, Huijing He, Yaoda Hu, Ji Tu, Ling Zhang, Ze Cui, Xiaolan Ren, Xianghua Wang, Jing Nai, Guangliang Shan","doi":"10.1111/ahg.12578","DOIUrl":"https://doi.org/10.1111/ahg.12578","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the heritability of various obesity indices and their shared genetic factors with cardiometabolic traits in the Chinese nuclear family.</p><p><strong>Methods: </strong>A total of 1270 individuals from 538 nuclear families were included in this cross-sectional study. Different indices were used to quantify fat mass and distribution, including body index mass (BMI), visceral fat index (VFI), and body fat percent (BFP). Heritability and genetic correlations for all quantitative traits were estimated using variance component models. The susceptibility-threshold model was utilized to estimate the heritability for binary traits.</p><p><strong>Results: </strong>Heritability estimates for obesity indices were highest for BMI (59%), followed by BFP (49%), and VFI (40%). Heritability estimates for continuous cardiometabolic traits varied from 24% to 50%. All obesity measures exhibited consistently significant positive genetic correlations with blood pressure, fasting blood glucose, and uric acid (r<sub>G</sub> range: 0.26-0.57). However, diverse genetic correlations between various obesity indices and lipid profiles were observed. Significant genetic correlations were limited to specific pairs: BFP and total cholesterol (r<sub>G</sub> = 0.24), BFP and low-density lipoprotein cholesterol (r<sub>G</sub> = 0.25), and VFI and triglyceride (r<sub>G</sub> = 0.33).</p><p><strong>Conclusion: </strong>The genetic overlap between various obesity indices and cardiometabolic traits underscores the importance of pleiotropic genes. Further studies are warranted to investigate specific shared genetic and environmental factors between obesity and cardiometabolic diseases.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139101","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}
引用次数: 0
Spinocerebellar ataxia type 10 and Huntington disease-like 2 in Venezuela: Further evidence of two different ancestral founder effects 委内瑞拉的脊髓小脑共济失调 10 型和亨廷顿病样 2:两种不同祖先奠基效应的进一步证据。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-08-30 DOI: 10.1111/ahg.12576
Irene Paradisi, Sergio Arias, Vassiliki Ikonomu
{"title":"Spinocerebellar ataxia type 10 and Huntington disease-like 2 in Venezuela: Further evidence of two different ancestral founder effects","authors":"Irene Paradisi,&nbsp;Sergio Arias,&nbsp;Vassiliki Ikonomu","doi":"10.1111/ahg.12576","DOIUrl":"10.1111/ahg.12576","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub-Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease-like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub-Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In-phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus-specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Knowing the genetic ancestry and geographic origins of patients in Ibero-American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103763","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}
引用次数: 0
Effects of BRCA variation on prognosis in patients with nonmetastatic breast cancer BRCA 变异对非转移性乳腺癌患者预后的影响。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-08-29 DOI: 10.1111/ahg.12577
Alper Türkel, Ilknur Deliktaş Onur, Hicran Anik, Irem Öner, Haktan Bağiş Erdem, Taha Bahsi, Özge Özalp, Berna Öksüzoğlu, Öztürk Ateş, Cengiz Karaçin
{"title":"Effects of BRCA variation on prognosis in patients with nonmetastatic breast cancer","authors":"Alper Türkel,&nbsp;Ilknur Deliktaş Onur,&nbsp;Hicran Anik,&nbsp;Irem Öner,&nbsp;Haktan Bağiş Erdem,&nbsp;Taha Bahsi,&nbsp;Özge Özalp,&nbsp;Berna Öksüzoğlu,&nbsp;Öztürk Ateş,&nbsp;Cengiz Karaçin","doi":"10.1111/ahg.12577","DOIUrl":"10.1111/ahg.12577","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>To compare the clinicopathological characteristics of nonmetastatic breast cancer patients with and without BRCA variations and to investigate the impact of BRCA variations on prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective single-center study involved an analysis of 938 patients with localized or locally advanced breast cancer who underwent BRCA variation testing. The patients were divided into three groups: 757 were without BRCA variation, 64 were with BRCA1 variation, and 117 were with BRCA2 variation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In patients with BRCA1 variation, the Ki67, grade, and frequency of triple-negative breast cancer were significantly higher than in patients without BRCA variation and with BRCA2 variation. The 5-year disease-free survival in patients with BRCA1 variation was significantly worse than the other two groups (without BRCA, BRCA1, and BRCA2; 87.7%, 69.9%, and 95.3%, respectively, <i>p</i> = 0.049). Multivariate analysis detected no significant difference between groups. The pathological complete response rates with neoadjuvant therapy were significantly better in patients with BRCA variations than those without BRCA variations (49.2% vs. 29.6%, <i>p</i> = 0.024).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Patients with BRCA1 variation had more aggressive tumor characteristics, such as higher Ki67 and higher grade. Also, triple-negative breast cancer was more common. The presence of BRCA1 variation may worsen survival outcomes. Neoadjuvant treatment responses of patients with BRCA variations were significantly better, and neoadjuvant treatment may contribute to survival outcomes in nonmetastatic patients with BRCA variations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103762","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}
引用次数: 0
The molecular basis of lactase persistence: Linking genetics and epigenetics. 乳糖酶持久性的分子基础:将遗传学和表观遗传学联系起来。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-08-22 DOI: 10.1111/ahg.12575
Céleste E Cohen, Dallas M Swallow, Catherine Walker
{"title":"The molecular basis of lactase persistence: Linking genetics and epigenetics.","authors":"Céleste E Cohen, Dallas M Swallow, Catherine Walker","doi":"10.1111/ahg.12575","DOIUrl":"https://doi.org/10.1111/ahg.12575","url":null,"abstract":"<p><p>Lactase persistence (LP) - the genetic trait that determines the continued expression of the enzyme lactase into adulthood - has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016176","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}
引用次数: 0
First report of an Ivorian family with nonsyndromic hearing loss caused by GJB2 compound heterozygous variants. 首次报告科特迪瓦一个家族因 GJB2 复合杂合变异而导致非综合征性听力损失。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-08-02 DOI: 10.1111/ahg.12574
Madoussou Toure, Ghita Amalou, Imane Ait Raise, N'kan Max Ange Mobio, Abderrahim Malki, Abdelhamid Barakat
{"title":"First report of an Ivorian family with nonsyndromic hearing loss caused by GJB2 compound heterozygous variants.","authors":"Madoussou Toure, Ghita Amalou, Imane Ait Raise, N'kan Max Ange Mobio, Abderrahim Malki, Abdelhamid Barakat","doi":"10.1111/ahg.12574","DOIUrl":"https://doi.org/10.1111/ahg.12574","url":null,"abstract":"<p><p>The primary etiology of congenital hearing loss is attributed to genetic factors, with GJB2 identified as a pivotal gene across diverse ethnic groups. Additionally, nonsyndromic hearing loss is predominantly inherited in an autosomal recessive manner. We used Sanger sequencing to analyze GJB2 in 17 deaf children from 13 unrelated Ivory Coast families. One family had two children born with severe congenital deafness and exhibited pathogenic compound heterozygous variants. These variants included a nonsense substitution (c.132G > A or p.Trp44Ter) and a newly discovered duplication of 7 base pairs (c.205_211dupTTCCCCA or p.Ser72ProfsTer32). Segregation testing confirmed these variants, marking the first identification of GJB2 in an Ivorian family with congenital hearing loss.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873987","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}
引用次数: 0
Methods for multiancestry genome-wide association study meta-analysis. 多家系全基因组关联研究荟萃分析方法。
IF 1 4区 生物学
Annals of Human Genetics Pub Date : 2024-07-18 DOI: 10.1111/ahg.12572
Chuan Fu Yap, Andrew P Morris
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