Annals of Human Genetics最新文献

{"title":"The systematic identification of survival-related alternative splicing events and splicing factors in glioblastoma","authors":"Tao Peng,&nbsp;Zhe Liu,&nbsp;Yu Zhang,&nbsp;Xudong Liu,&nbsp;Lijun Zhao,&nbsp;Ying Ma,&nbsp;Jinke Fan,&nbsp;Xinqiang Song,&nbsp;Lei Wang","doi":"10.1111/ahg.12550","DOIUrl":"10.1111/ahg.12550","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, making it one of the most life-threatening human cancers. Nevertheless, research on the mechanism of action between alternative splicing (AS) and splicing factor (SF) or biomarkers in GBM is limited. AS is a crucial post-transcriptional regulatory mechanism. More than 95% of human genes undergo AS events. AS can diversify the expression patterns of genes, thereby increasing the diversity of proteins and playing a significant role in the occurrence and development of tumors. In this study, we downloaded 599 clinical data and 169 transcriptome analysis data from The Cancer Genome Atlas (TCGA) database. Besides, we collected AS data about GBM from TCGA-SpliceSeq. The overall survival (OS) related AS events in GBM were determined through least absolute shrinkage and selection operator (Lasso) and Cox analysis. Subsequently, the association of these 1825 OS-related AS events with patient survival was validated using the Kaplan–Meier survival analysis, receiver operating characteristic curve, risk curve analysis, and independent prognostic analysis. Finally, we depicted the AS–SF regulatory network, illustrating the interactions between splicing factors and various AS events in GBM. Additionally, we identified three splicing factors (<i>RNU4-1</i>, <i>SEC31B</i>, and <i>CLK1</i>) associated with patient survival. In conclusion, based on AS occurrences, we developed a predictive risk model and constructed an interaction network between GBM-related AS events and SFs, aiming to shed light on the underlying mechanisms of GBM pathogenesis and progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 4","pages":"320-335"},"PeriodicalIF":1.9,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899255","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":"Association of blood lipid profiles and asthma: A bidirectional two-sample Mendelian randomization study","authors":"Yi-Shian Liu,&nbsp;Yu-Chun Lin,&nbsp;Meng-Chih Lin,&nbsp;Chao-Chien Wu,&nbsp;Tsu-Nai Wang","doi":"10.1111/ahg.12545","DOIUrl":"10.1111/ahg.12545","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Observational studies and meta-analyses have indicated associations between blood lipid profiles and asthma. However, the causal association is unknown. Therefore, this study investigated the causal relationship between blood lipid profiles and asthma using bidirectional Mendelian randomization analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and materials</h3>\u0000 \u0000 <p>Our analyses were performed using individual data from the Taiwan Biobank and summary statistics from the Asian Genetic Epidemiology Network (AGEN). The causal estimates between all genetic variants, exposures of interest and asthma were calculated using an inverse-variance weighted method based on Taiwan Biobank data from 24,853 participants (mean age, 48.8 years; 49.8% women). Sensitivity analyses, including the weighted median, MR Egger regression, MR-PRESSO, mode-based estimate, contamination mixture methods, and leave-one-out analysis, were applied to validate the results and detect pleiotropy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the inverse-variance weighted (IVW) analyses, we found evidence of a significant causal effect of an increased level of low-density lipoprotein cholesterol on asthma risk (<i>β</i>_IVW = 1.338, <i>p</i> = 0.001). A genetically decreased level of high-density lipoprotein cholesterol was also associated with asthma risk (<i>β</i>_IVW = −0.338, <i>p</i> = 0.01). We also found that an increased level of total cholesterol was associated with an increased risk of asthma (<i>β</i>_IVW = 1.343, <i>p</i> = 0.001). Several sensitivity analyses generated consistent findings. We did not find evidence to support the causality between asthma and blood lipid profiles in either direction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results supported the causal relationship between higher levels of LDL cholesterol and total cholesterol and lower levels of HDL cholesterol with an increased risk of asthma.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 4","pages":"307-319"},"PeriodicalIF":1.9,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668876","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":"ABCA1 variant rs9282541 is associated with metabolic syndrome in Maya children","authors":"Barbara I. Peña-Espinoza,&nbsp;Emmanuel Torre-Horta,&nbsp;María G. Ortiz-López,&nbsp;Marta Menjivar","doi":"10.1111/ahg.12546","DOIUrl":"10.1111/ahg.12546","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Metabolic syndrome (MetS) is a metabolic disorder encompassing risk factors for cardiovascular disease and type 2 diabetes (T2D). In Mexico, the MetS is a national health problem in adults and children. Environmental and genetic factors condition the MetS. However, studies to elucidate the contribution of genetic factors to MetS in Mexico are scarce. A recent study showed that variant rs9282541 (A-allele) in ATP-binding cassette transporter A1 (<i>ABCA1</i>) was associated with T2D in the Maya population in addition to low levels of high-density lipoprotein cholesterol (HDL-C). Thus, this study aimed to determine whether the genetic variant of <i>ABCA1</i> A-allele (rs9282541, NM_005502.4:c.688C &gt; T, NP_005493.2:p.Arg230Cys) is associated with MetS and its components in Mexican Maya children.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study was conducted in 508 children aged 9–13 from the Yucatán Peninsula. MetS was identified according to the de Ferranti criteria. Genotyping was performed using TaqMan assay by real-time PCR. Evaluation of genetic ancestry group was included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The frequency of MetS and overweight–obesity was 45.9% and 41.6%, respectively. The genetic variant rs9282541 was associated with low HDL-C and high glucose concentrations. Remarkably, for the first time, this study showed the association of <i>ABCA1</i> rs9282541 with MetS in Maya children with an OR of 3.076 (95% CI = 1.16–8.13 <i>p</i> = 0.023). Finally, this study reveals a high prevalence of MetS and suggests that variant rs9282541 of the <i>ABCA1</i> gene plays an important role in the developing risk of MetS in Maya children.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 4","pages":"279-286"},"PeriodicalIF":1.9,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401562","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":"Investigation of the association between the Toll-like receptor 1 rs4833095 variation and gastric adenocarcinoma recurrence","authors":"Yuan Dang,&nbsp;Jingyun Huang,&nbsp;Chen Lin,&nbsp;Shaohua Xu","doi":"10.1111/ahg.12548","DOIUrl":"10.1111/ahg.12548","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Toll-like receptors (TLRs) are a family of transmembrane receptors that play key roles in identifying invading pathogens and activating innate immunity. TLR1 has been reported to be associated with the risk of gastric cancer (GC) but that was based on only a simple statistical analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We genotyped the TLR1 in 526 GC patients to investigate the association between the variation and gastric cancer survival by the multiplex polymerase chain reaction and sequencing method. The rs4833095 variation (chr4:38798089 [GRCh38. p14], T &gt; C) in the <i>TLR1</i> gene was genotyped in 526 patients who underwent GC resection. The associations between genotype, survival, and recurrence were investigated. The potential role of TLR1 in stomach cancer was investigated using clinical data from formalin-fixed, paraffin-embedded tissue samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with the T/C and C/C genotypes of rs4833095 had a lower risk of recurrence than those with the T/T genotype. Recurrence-free periods were substantially longer in patients with the T/C or C/C genotypes (22.6 and 22.3 months, respectively) than in those with the T/T genotype (20.7 months). Patients with the T/C or C/C genotype, low expression levels of <i>VEGF1</i>, high expression levels of <i>ERBB2</i> and <i>ERCC1</i>, the absence of cancer nodules, a tumor size of less than 5 cm, and poor differentiation had a considerably reduced risk of recurrence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>TLR1</i> rs4833095 was correlated with the postresection prognosis of patients with gastric cancer, suggesting that TLR1 may have a role in the onset or progression of gastric cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 4","pages":"287-299"},"PeriodicalIF":1.9,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401572","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":"Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer","authors":"Zhaokun Wang,&nbsp;Jiaying Shi,&nbsp;Dachang Tao,&nbsp;Shengyu Xie,&nbsp;Yuan Yang,&nbsp;Yunqiang Liu","doi":"10.1111/ahg.12549","DOIUrl":"10.1111/ahg.12549","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of <i>BMPR1A</i> lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the <i>BMPR1A</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A novel nonsense variant (c.1114A &gt; T, p.Lys372*) of <i>BMPR1A</i> was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The identification of the novel <i>BMPR1A</i> variant enriched the genotype–phenotype spectrum of <i>BMPR1A</i>. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 4","pages":"300-306"},"PeriodicalIF":1.9,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401573","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":"A comprehensive review of HVS-I mitochondrial DNA variation of 19 Iranian populations","authors":"Motahareh Amjadi,&nbsp;Zahra Hayatmehr,&nbsp;Balázs Egyed,&nbsp;Mahmood Tavallaei,&nbsp;Anna Szécsényi-Nagy","doi":"10.1111/ahg.12544","DOIUrl":"10.1111/ahg.12544","url":null,"abstract":"<p>Iran is located along the Central Asian corridor, a natural artery that has served as a cross-continental route since the first anatomically modern human populations migrated out of Africa. We compiled and reanalyzed the HVS-I (hypervariable segment-I) of 3840 mitochondrial DNA (mtDNA) sequences from 19 Iranian populations and from 26 groups from adjacent countries to give a comprehensive review of the maternal genetic variation and investigate the impact of historical events and cultural factors on the maternal genetic structure of modern Iranians. We conclude that Iranians have a high level of genetic diversity. Thirty-six haplogroups were observed in Iran's populations, and most of them belong to widespread West-Eurasian haplogroups, such as H, HV, J, N, T, and U. In contrast, the predominant haplogroups observed in most of the adjacent countries studied here are H, M, D, R, U, and C haplogroups. Using principal component analysis, clustering, and genetic distance-based calculations, we estimated moderate genetic relationships between Iranian and other Eurasian groups. Further, analyses of molecular variance and comparing geographic and genetic structures indicate that mtDNA HVS-I sequence diversity does not exhibit any sharp geographic structure in the country. Barring a few from some culturally distinct and naturally separated minorities, most Iranian populations have a homogenous maternal genetic structure.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 3","pages":"259-277"},"PeriodicalIF":1.9,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139071378","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":"Using the Bayesian variational spike and slab model in a genome-wide association study for finding associated loci with bipolar disorder","authors":"Maryam Kazemi Naeini,&nbsp;Mahdi Akbarzadeh,&nbsp;Iraj Kazemi,&nbsp;Doug Speed,&nbsp;Sayed Mohsen Hosseini","doi":"10.1111/ahg.12538","DOIUrl":"10.1111/ahg.12538","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The genome-wide association studies (GWAS) analysis, the most successful technique for discovering disease-related genetic variation, has some statistical concerns, including multiple testing, the correlation among variants (single-nucleotide polymorphisms) based on linkage disequilibrium and omitting the important variants when fitting the model with just one variant. To eliminate these problems in a small sample-size study, we used a sparse Bayesian learning model for finding bipolar disorder (BD) genetic variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study used the Wellcome Trust Case Control Consortium data set, including 1998 BD cases and 1500 control samples, and after quality control, 380,628 variants were analysed. In this GWAS, a Bayesian logistic model with hierarchical shrinkage spike and slab priors was used, with all variants considered simultaneously in one model. In order to decrease the computational burden, an alternative inferential method, Bayesian variational inference, has been used.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Thirteen variants were selected as associated with BD. The three of them (rs7572953, rs1378850 and rs4148944) were reported in previous GWAS. Eight of which were related to hemogram parameters, such as lymphocyte percentage, plateletcrit and haemoglobin concentration. Among selected related genes, GABPA, ELF3 and JAM2 were enriched in the platelet-derived growth factor pathway. These three genes, along with APP, ARL8A, CDH23 and GPR37L1, could be differential diagnostic variants for BD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>By reducing the statistical restrictions of GWAS analysis, the application of the Bayesian variational spike and slab models can offer insight into the genetic link with BD even with a small sample size. To uncover related variations with other traits, this model needs to be further examined.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 3","pages":"212-246"},"PeriodicalIF":1.9,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139071459","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":"Exploring the clinical significance of miR-148 expression variations in distinct subtypes of irritable bowel syndrome","authors":"Qun Ji,&nbsp;Fengxia Du,&nbsp;Yangyaxin Yu,&nbsp;Ying Li","doi":"10.1111/ahg.12543","DOIUrl":"10.1111/ahg.12543","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Irritable bowel syndrome (IBS) belongs to chronic functional gastrointestinal diseases featured by abdominal pain and changes in bowel habits. This study aimed to investigate the clinical significance of serum miR-148 expression in different subtypes of IBS. We enrolled 86 IBS patients and 55 healthy controls. miR-148 expression levels were assessed in IBS patients classified into IBS-constipation (IBS-C), IBS-diarrhea (IBS-D), and IBS-mixed stool pattern (IBS-M) subtypes. Receiver-operating characteristic (ROC) curves were employed to evaluate the diagnostic potential of miR-148 in distinguishing among IBS subtypes. Additionally, we analyzed the correlation between miR-148 expression and clinical characteristics, including IBS symptom severity. miR-148 expression was highest in IBS-D (diarrhea) group, followed by IBS-M and IBS-C. With the exception of the IBS-C group, miR-148 expression was elevated in IBS patients compared to controls. ROC curve analysis demonstrated that serum miR-148 exhibited higher diagnostic accuracy for discriminating IBS-C and IBS-D than IBS-M. Correlation analysis revealed a positive relationship between serum miR-148 relative expression and IBS symptom severity system scores. Univariate logistic analysis indicated a positive association between miR-148 expression and IBS-D and a negative correlation with IBS-C. miR-148 expression exhibits differential patterns among IBS subtypes and holds a potential to distinguish IBS-C and IBS-D. Furthermore, miR-148 expression correlates with the severity of IBS symptoms.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 3","pages":"247-258"},"PeriodicalIF":1.9,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139071625","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":"Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment","authors":"Boudour Khabou,&nbsp;Fakhri Kallabi,&nbsp;Rim Ben Abdelaziz,&nbsp;Ines Maaloul,&nbsp;Hajer Aloulou,&nbsp;Amel ben Chehida,&nbsp;Thouraya Kammoun,&nbsp;Veronique Barbu,&nbsp;Tahya Sellami Boudawara,&nbsp;Faiza Fakhfakh,&nbsp;Bassem Khemakhem,&nbsp;Olfa Siala Sahnoun","doi":"10.1111/ahg.12542","DOIUrl":"10.1111/ahg.12542","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel–target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the <i>ABCB11</i> gene and the p.Arg446 * in the <i>ABCC2</i> gene), a novel p.Ala98Cys variant in the <i>ATP-binding cassette subfamily G member 5</i> (<i>ABCG5)</i> gene and a first homozygous description of the p.Gln312His in the <i>ABCB11</i> gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the <i>ABCC2</i> gene) and functionality (p.Asp19His in the <i>ABCG8</i> gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 3","pages":"194-211"},"PeriodicalIF":1.9,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138798646","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":"Cover Image, Volume 88, Issue 1","authors":"","doi":"10.1111/ahg.12547","DOIUrl":"10.1111/ahg.12547","url":null,"abstract":"<p><b>On the cover</b>: The cover image is based on the Review Article <i>The molecular structure and function of fibrocystin, the key gene product implicated in autosomal recessive polycystic kidney disease (ARPKD)</i> by Travis A K Bannell et al., https://doi.org/10.1111/ahg.12535. \u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138632693","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}