Annals of Human Genetics最新文献

{"title":"RETRACTION: Investigating the Effectiveness of Forensic Genetics and Population Genetic Diversity Using a Multi-InDel System in Chinese Hezhou and Southern Shaanxi Han Populations.","authors":"","doi":"10.1111/ahg.12590","DOIUrl":"https://doi.org/10.1111/ahg.12590","url":null,"abstract":"<p><strong>Retraction: </strong>Wang, X., Q. Lan, Y. Lin, et al. \"Investigating the Effectiveness of Forensic Genetics and Population Genetic Diversity Using a Multi-InDel System in Chinese Hezhou and Southern Shaanxi Han Populations,\" Annals of Human Genetics (Early View): https://doi.org/10.1111/ahg.12553. The above article, published online on 20 May 2024, in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by an agreement between the authors; the journal's Editor in Chief, Dr. Rosemary Ekong; University College London; and John Wiley & Sons, Ltd.  The authors reported that a number of errors had been included in the published article, which would require corrections to the abstract, results, and conclusions, as well as Figure 5. The editors confirmed these errors. The retraction has been agreed to because the corrections required to amend these major errors would require substantial changes to the results and conclusions in the article. The authors have agreed to submit the revised version of this article for evaluation by the journal.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998870","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":"Persistence of Ancestral KhoeSan Mitochondrial Patterns in Contemporary South African Populations.","authors":"Maria Eugenia D'Amato, Peter Ristow, Michelle Livesey, Kirsty Heynes, Nicole Huber, Claudio Bravi, Anders J Hansen, Walther Parson","doi":"10.1111/ahg.12589","DOIUrl":"https://doi.org/10.1111/ahg.12589","url":null,"abstract":"<p><strong>Introduction: </strong>Southern Africa has been inhabited by hunter-gatherers for at least 20,000 years and has received diverse immigration flows in the last 2000 years. The original inhabitants have interacted with the pastoralist migrants from Eastern Africa (∼2000 ybp), followed by the southern Bantu migration arriving some 1000 ybp, and more recently with the European and Asian settlers after the 17th century. Many of the original Khoekhoe and San inhabitants have either become extinct or have disappeared through admixture in South Africa (SA), in a sex-biased manner involving KhoeSan women.</p><p><strong>Methods: </strong>In this study, we generated mitochondrial DNA (mtDNA) control region (CR) sequences for 247 South African individuals. The sampling effort was concentrated in regions and populations with historical links to the KhoeSan population groups: admixed (Coloured, Griqua), Nama (Khoekhoe) and Bantu in three provinces. Here we evaluate the composition and extent of connectivity between population groups and regions, and to assess the distribution of haplotypes for the practical application of mtDNA CR data in forensic identifications.</p><p><strong>Results: </strong>The analysis of the newly generated sequences revealed 142 distinct haplotypes, of which 122 were unique. Haplogroup L0 was predominant (overall 71.7%). A high-frequency L0d2a haplotype dominated the pool of the admixed groups with 10%-12.5% incidence overall or per region. Comparative analysis with 545 extant mtDNA CR sequences from South African KhoeSan and admixed descendants revealed extensive population structure and high within-group haplotype sharing.</p><p><strong>Conclusion: </strong>The observed population and regional variations, combined with the prevalence of high-frequency haplotypes, align with patterns of matrilocality. These findings highlight the limitations of using mtDNA control region analysis for forensic applications in South Africa.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12589"},"PeriodicalIF":1.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943316","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":"Genotype and Haplotype Analysis With In Silico Prediction of TMPRSS2 Gene in Jordanian Population.","authors":"Razan Issam Abu-Almfalfal, Yazun Bashir Jarrar, Munir Gharaibeh","doi":"10.1111/ahg.12588","DOIUrl":"https://doi.org/10.1111/ahg.12588","url":null,"abstract":"<p><strong>Background: </strong>The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health concern. The entry of the virus into host cells is facilitated by the transmembrane protease serine 2 (TMPRSS2) receptor, and genetic variations in the TMPRSS2 gene may influence disease susceptibility. However, there is a lack of knowledge regarding TMPRSS2 genetic variants and haplotypes in the Jordanian population.</p><p><strong>Aims: </strong>This study aimed to characterize the genotype and haplotype variations in the TMPRSS2 binding domain with SARS-CoV-2 among Jordanian volunteers.</p><p><strong>Methods: </strong>The binding domain of TMPRSS2 with SARS-CoV-2 (Exons 9 and 10) was amplified using polymerase chain reaction (PCR) for a random sample of 120 healthy unrelated Jordanian volunteers, followed by Sanger DNA sequencing for the PCR products. The effect of the novel genetic variants on the TMPRSS2 protein structure was predicted using in silico methods.</p><p><strong>Results: </strong>The results showed significant (p < 0.05, chi-square) allele frequencies for known TMPRSS2 variants, with c.888C > T being the most prevalent among Jordanian volunteers. Novel genetic variants, including c.869A > G and c.923T > A, were also identified, with the latter being the most common novel variant. Haplotype analysis showed that the most prevalent TMPRSS2 haplotype is c.911G/1051A/1052T/1010 + 45C/1011 - 38T/1011 - 52C/1011 - 54A. In silico programs predicted that TMPRSS2 c.923T > A and c.1052T > A variants affect transmembrane proteins and catalytic sites.</p><p><strong>Conclusions: </strong>This research provides information about the gene structure of the TMPRSS2 binding domain in Jordanians. Some of the identified variants, especially c.923T > A, may influence protein function, warranting further in vitro and in vivo investigations. In addition, further clinical research studies are needed to link the identified TMPRSS2 variants with COVID-19 susceptibility and severity among Jordanians.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891545","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":"Identifying a Genetic Link Between Lung Function and Psoriasis.","authors":"Kazuya Tanimura, Melinda C Aldrich, James Jaworski, Jinchuan Xing, Satoshi Okawa, Divay Chandra, Seyed M Nouraie, Toru Nyunoya","doi":"10.1111/ahg.12587","DOIUrl":"https://doi.org/10.1111/ahg.12587","url":null,"abstract":"<p><strong>Introduction: </strong>The common genetic underpinnings of psoriasis and pulmonary comorbidities have yet to be explored.</p><p><strong>Material and methods: </strong>In this cross-sectional study, we investigated the single-nucleotide polymorphisms (SNPs) associated with psoriasis and their relationship with pulmonary function using data from the UK Biobank (UKBB) and the Vanderbilt University Medical Center Biobank (BioVU).</p><p><strong>Results: </strong>Out of the 63 psoriasis-associated SNPs identified in previous genome-wide association studies within the European population, we successfully identified 53 SNPs, including proxy SNPs in UKBB database. Following adjustments using age and sex, 31 SNPs displayed statistically significant associations with psoriasis. Among these, 16 SNPs exhibited significant associations with forced expiratory volume in 1 s (FEV₁), 14 with forced vital capacity (FVC), and 5 with the FEV₁/FVC ratio in the UKBB. In the validation analysis using the BioVU database, 27 of the 31 psoriasis-associated SNPs were available for examination. Notably, the minor allele of SNP rs8016947 was confirmed to be significant, indicating a reduced risk for psoriasis and improved FEV₁. Similarly, the minor alleles of SNPs rs17716942 and rs8016947 were associated with a reduced risk of psoriasis and enhanced FVC. However, none of the 5 SNPs significantly associated with the FEV₁/FVC ratio in the UKBB displayed significance in the BioVU dataset.</p><p><strong>Conclusion: </strong>This study has unveiled genetic variants that bridge the realms of psoriasis and lung function. The genes associated with these variants, including IFIH1, Grancalcin gene (GCA), and NFKB inhibitor alpha gene (NFKBIA), regulate innate immune responses, which suggests that immunodysregulation, a central element in psoriasis pathogenesis, may also impact lung function, alluding to a \"skin-lung axis.\"</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881142","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":"Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review.","authors":"Namanpreet Kaur, Puneeth H Somashekar, Sekar Deepha, Periyasamy Govindaraj, Anju Shukla, Siddaramappa J Patil","doi":"10.1111/ahg.12585","DOIUrl":"https://doi.org/10.1111/ahg.12585","url":null,"abstract":"<p><strong>Introduction: </strong>Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine-threonine kinase domain 2 (FASTKD2) (MIM# 612322). COXPD44 is characterized by variable clinical features-developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sib with episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes.</p><p><strong>Material and methods: </strong>Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling.</p><p><strong>Results: </strong>WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts.</p><p><strong>Conclusion: </strong>Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685868","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":"Secondary findings in 443 exome sequencing data.","authors":"Marija Branković, Heonjong Han, Milena Janković, Ana Marjanović, Nikola Andrejic, Ilija Gunjić, Vanja Virić, Aleksa Palibrk, Hane Lee, Stojan Peric","doi":"10.1111/ahg.12586","DOIUrl":"https://doi.org/10.1111/ahg.12586","url":null,"abstract":"<p><p>Exome sequencing (ES) may identify and report secondary findings that are unrelated to the primary disease for which the patient underwent genetic testing, but are of potential value in patient care. In this study, we evaluated 81 American College of Medical Genetics (ACMG) medically actionable genes in 443 patients with various neurological disorders. The variants identified were classified and reported following the 2015 ACMG Standards and Guidelines for the interpretation of sequence variants and the ACMG recommendations for reporting secondary findings (v3.2). We detected a total of 17 variants in 17 patients across 9 different genes as secondary findings. Seven heterozygous variants were found in BRCA1, MSH2, and PALB2 which are part of the cancer phenotype category. Nine heterozygous variants were found in MYH7, TTN, LDLR, DSC2, and DSP which are part of the cardiovascular phenotype category. Finally, one heterozygous variant was found in TTR which is part of the miscellaneous phenotype category. Thirteen of above mentioned variants were classified as known pathogenic and four as expected pathogenic. The information collected in our study may lead to the prevention of severe morbidity and mortality and provides additional insight into the genetic background of the Serbian population.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638061","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":"Gastroesophageal reflux disease increases predisposition to severe COVID-19: Insights from integrated Mendelian randomization and genetic analysis","authors":"Jingjing Pan,&nbsp;Jianhua Li","doi":"10.1111/ahg.12584","DOIUrl":"10.1111/ahg.12584","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aims to investigate the potential causal relationship, shared genomic loci, as well as potential molecular pathways and tissue-specific expression patterns between gastroesophageal reflux disease (GERD) and the risk of hospitalized/severe 2019 coronavirus disease (COVID-19).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) analysis to explore potential genetic associations between GERD (<i>N</i> = 602,604) and hospitalized COVID-19 (<i>N</i> = 2095,324) as well as severe COVID-19 (<i>N</i> = 1086,211). Additionally, shared genomic loci were extracted from common pivotal regions, further confirmed through corresponding colocalization analyses. GERD-driven molecular pathway network was constructed using extensive literature data mining to understand the molecular-level impacts of GERD on COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our results revealed a significant positive genetic correlation between GERD and both hospitalized (<i>r_g</i>  =  0.418) and severe COVID-19 (<i>r_g</i>  =  0.314). Furthermore, the MR analysis demonstrated a unidirectional causal effect of genetic predisposition to GERD on COVID-19 outcomes, including hospitalized COVID-19 (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.27–1.44, <i>p</i> = 9.17e − 12) and severe COVID-19 (OR: 1.27, 95% CI: 1.18–1.37, <i>p</i> = 1.20e − 05). Additionally, GERD and both COVID-19 conditions shared one genomic locus with lead-SNPs rs1011407 and rs1123573, corresponding to the transcription factor BCL11A. Colocalization analysis further demonstrated a significant positive correlation between genome-wide association study and expression quantitative trait locus (eQTL) abnormalities, including rs1011407 (eQTL_<i>p</i> = 2.35e − 07) and rs1123573 (eQTL_<i>p</i> = 2.74e − 05). Molecular pathway analysis indicated that GERD might promote the progression of COVID-19 by inducting immune-activated and inflammation-related pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings confirm that genetically determined GERD may increase the susceptibility to hospitalized/severe COVID-19. The shared genetic loci and the potential molecular pathways offer valuable insights into causal connections between GERD and COVID-19.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 1","pages":"54-65"},"PeriodicalIF":1.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12584","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613676","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":"Clinical and immunological features of four patients with activation-induced cytidine deaminase deficiency: Renal amyloidosis and other presentations","authors":"Safa S. Meshaal,&nbsp;Rabab E. El Hawary,&nbsp;Dalia S. Abd Elaziz,&nbsp;Alia Eldash,&nbsp;Rania Darwish,&nbsp;Aya Erfan,&nbsp;Sohilla Lotfy,&nbsp;Mai M. Saad,&nbsp;Engy A. Chohayeb,&nbsp;Mohamed S. Nagy,&nbsp;Radwa Alkady,&nbsp;Jeannette A. Boutros,&nbsp;Nermeen M. Galal,&nbsp;Aisha M. Elmarsafy","doi":"10.1111/ahg.12583","DOIUrl":"10.1111/ahg.12583","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p><i>Activation-induced cytidine deaminase (AID)</i> deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by increased susceptibility to infections, autoimmunity, and/or autoinflammation. <i>AID</i> plays an important role in immunoglobulin class switching and somatic hypermutation. <i>AID</i> deficiency patients have very low or absent levels of IgG, IgA, and IgE, while IgM level is elevated. The disease is designated as type 2 hyperimmunoglobulin M syndrome (HIGM-2). To date, around 130 patients with HIGM-2 have been reported, none from Egypt.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Four patients from three different consanguineous families with elevated serum IgM and low IgG and IgA were included in the study. After the exclusion of CD40 and/or CD40L deficiency by flow cytometry, patients’ samples were tested by a panel covering 452 genes (four bases PID-Pro) on the Illumina Miseq platform.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>All patients suffered repeated infections since childhood. Patients 1–3 had inflammatory bowel disease-like (IBD-like) symptoms, while patient 4 did not have autoimmune manifestations. Patient 1 is the first HIGM-2 patient to be reported to have renal amyloidosis as part of the autoinflammation. Patients 1–3 had the same pathogenic variant (NM_020661.4 (<i>AID</i>):c.406del, p.Ile136Ter), while patient 4 had another pathogenic variant (NM_020661.4 (<i>AID</i>):c.374G &gt; A, p.Gly125Glu). The variant p.Ile136Ter was not reported before in any of the documented HIGM-2 patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HIGM-2 is a rare IEI that can be overlooked; hence, patients’ diagnosis is delayed. Autoimmune and autoinflammatory manifestations develop later in the disease course leading to significant morbidities. The diagnosis can be suspected after exclusion of CD40/CD40L deficiencies by flow cytometry, and the diagnosis can be confirmed by genetic testing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 1","pages":"47-53"},"PeriodicalIF":1.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602847","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":"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":" ","pages":""},"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}

{"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,&nbsp;Navneesh Yadav,&nbsp;Chandru Jayashankaran,&nbsp;Jeffrey Justin Margret,&nbsp;Mathuravalli Krishnamoorthy,&nbsp;Sorna Lakshmi A,&nbsp;Chandralekha Meenakshi Sundaram,&nbsp;N. P. Karthikeyan,&nbsp;B. K. Thelma,&nbsp;C. R. Srikumari Srisailapathy","doi":"10.1111/ahg.12579","DOIUrl":"10.1111/ahg.12579","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Developmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in <i>GNPTAB, GNPTG</i>, and <i>NAGPA</i> involved in lysosomal pathway and <i>AP4E1, IFNAR1</i>, and <i>ARMC3-</i>signaling genes reported till date explain only ∼2.1% – 3.7% of persistent stuttering cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>We aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (<i>n</i> = 27) and further validation on additional extended family members (<i>n</i> = 21).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials &amp; Methods</h3>\u0000 \u0000 <p>We employed hypothesis-free and pathway-based analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A novel heterozygous exonic variant NM_016256.4:c.322G &gt; A in <i>NAGPA</i> 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 <i>RIMS2</i> and <i>XYLT1</i> in severely affected members; and <i>IGF2R</i> variant in a small subset of the family. Furthermore, pathway-based analysis uncovered NM_022089.4:c.3529G &gt; A in <i>ATP13A2</i> (<i>PARK9</i>) in affected members; and variants in G<i>NPTAB</i> and <i>GNPTG</i> of minor significance in a few affected members.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>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 <i>ATP13A2</i>, a Parkinson's disease gene also implicated in lysosomal dysfunction, and <i>RIMS2</i> suggests for the first time a likely role of dopamine signaling in stuttering.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Screening for these variants in independent stuttering cohorts would be astute.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 1","pages":"31-46"},"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}