Human Mutation最新文献

{"title":"Homozygous HOXC13 Variant Causes Pure Hair and Nail Ectodermal Dysplasia via Reduction in Protein Stability","authors":"Virginia Clowes,&nbsp;Xiaolun Ma,&nbsp;Hannah Maude,&nbsp;Catherine Dennis,&nbsp;Qing Gao,&nbsp;Geraldine Quinn,&nbsp;Edel A. O’Toole,&nbsp;Kapila Batta,&nbsp;Inês Cebola,&nbsp;Wei Cui","doi":"10.1155/2024/6420246","DOIUrl":"https://doi.org/10.1155/2024/6420246","url":null,"abstract":"<p>Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder characterized by reduced or absent hair and dystrophic nails. PHNED is caused by pathogenic variants in genes involved in hair and nail development, including <i>HOXC13</i>. Previously reported biallelic <i>HOXC13</i> pathogenic variants led to PHNED by either disrupting protein expression through nonsense-mediated decay or altering the DNA-binding affinity of the homeobox domain of HOXC13. Here, we report a case of <i>HOXC13</i>-related PHNED with a rare homozygous variant, c.931C&gt;T, p.Arg311Trp. Similarly to previously reported missense variants, p.Arg311Trp resides in the homeobox domain of HOXC13 and was assumed to lead to the decreased transcriptional activity of target genes. However, in contrast with previously reported variants, <i>in vitro</i> overexpression assays revealed that the p.Arg311Trp variant decreases HOXC13 protein stability, which is corroborated by a series of <i>in silico</i> predictions. Computational models further suggest that p.Arg311Trp results in a structural rearrangement with loss of interhelical connection between Arg311 in <i>α</i>-helix 3 and Glu276 in <i>α</i>-helix 1. Altogether, our results suggest a novel molecular mechanism causative of PHNED, whereby biallelic pathogenic variants in <i>HOXC13</i> may result in decreased protein stability and consequently decreased transcriptional activity of target genes essential for hair and nail development.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6420246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141487760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pi*S and Pi*Z Alleles of SERPINA1 Gene Are Associated With Specific Variants of a BRD4-Independent Enhancer","authors":"Ainhoa Escuela-Escobar,&nbsp;Esther Herrera-Luis,&nbsp;Elena Martín-González,&nbsp;José María Hernández-Pérez,&nbsp;Mario A. González Carracedo,&nbsp;José Antonio Pérez Pérez","doi":"10.1155/2024/6472805","DOIUrl":"https://doi.org/10.1155/2024/6472805","url":null,"abstract":"<p>Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by specific variants in the <i>SERPINA1</i> gene, which encodes AAT. The most common disease-associated <i>SERPINA1</i> variants are <i>Pi</i> ∗ <i>S</i> and <i>Pi</i> ∗ <i>Z</i> alleles, which cause moderate and severe AATD, respectively. Recent studies have reported the presence of a possible regulator of <i>SERPINA</i> gene cluster expression (LOC126862032), which is suggested to act as a BRD4-Independent Enhancer (<i>SERPINA</i>-BIE). This study is aimed at characterizing the <i>SERPINA</i>-BIE locus and assessing possible associations with <i>SERPINA1</i> AATD-related alleles. For this purpose, <i>SERPINA</i>-BIE was PCR genotyped from 917 samples, including 452 asthmatic patients, and 465 newborns. Nine <i>SERPINA</i>-BIE alleles were sequenced, revealing a specific combination of 56-bp sequence types, and each <i>SERPINA</i>-BIE allele has a unique total number of CpG sites. Statistical analyses revealed an association between the <i>Pi</i> ∗ <i>Z</i> allele of the <i>SERPINA1</i> gene and the <i>SERPINA</i>-BIE allele 13 (<i>p</i> value = 5.51 × 10⁻¹⁰), as well as between <i>Pi</i> ∗ <i>S</i> and <i>SERPINA</i>-BIE allele 14 (<i>p</i> value = 8.95 × 10⁻¹⁵). However, AAT levels were not associated with <i>SERPINA</i>-BIE alleles when models were corrected by <i>SERPINA1</i> genotypes. This study could contribute to a better understanding of the regulation of the <i>SERPINA1</i> gene expression, and its role in AATD.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6472805","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141488429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic Recessive Mutations in TLE6 and NLRP5 Cause Female Infertility Characterized by Human Early Embryonic Arrest","authors":"Ruiqi Li,&nbsp;Mei Mei,&nbsp;Ling Zhou,&nbsp;Haijing Zhao,&nbsp;Min Yang,&nbsp;Yingshi Li,&nbsp;Xiaoli Chen,&nbsp;Wenjun Wang,&nbsp;Ping Yuan","doi":"10.1155/2024/9278518","DOIUrl":"https://doi.org/10.1155/2024/9278518","url":null,"abstract":"<div>\u0000 <p>Preimplantation embryonic developmental arrest (EDA) is a common cause of unexplained female infertility. Genetic factors are believed to be one of the primary causes contributing to EDA. In this study, we identify four novel compound heterozygous mutations in <i>TLE6</i> and <i>NLRP5</i>, in two infertile female patients experiencing recurrent EDA, using whole-exome sequencing. Functional analysis revealed that the two splicing mutations in <i>TLE6</i> (c.541+2dupT) and <i>NLRP5</i> (c.2957+4A&gt;G) resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. <i>In vitro</i> experiments further validated that a missense mutation in <i>NLRP5</i> led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells. Immunofluorescence analysis confirmed the decay of the expression of TLE6 protein. Additionally, RNA sequencing results revealed significantly higher expression levels of some maternal genes in mutated embryos with <i>TLE6</i> mutations, possibly suggesting the disrupted clearance of maternal mRNA and the failure of embryo genome activation. These results highlight the role of biallelic recessive effects associated with <i>TLE6</i> and <i>NLRP5</i> variants in embryonic development, thereby widening the scope of the genetic landscape.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9278518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments","authors":"Bianca Zardetto,&nbsp;Willeke van Roon-Mom,&nbsp;Annemieke Aartsma-Rus,&nbsp;Marlen C. Lauffer","doi":"10.1155/2024/9933129","DOIUrl":"https://doi.org/10.1155/2024/9933129","url":null,"abstract":"<div>\u0000 <p>Neurodevelopmental disorders (NDDs) of genetic origin are a group of early-onset neurological diseases with highly heterogeneous etiology and a symptomatic spectrum that includes intellectual disability, autism spectrum disorder, and learning and language disorders. One group of rare NDDs is associated with dysregulation of the KMT2 protein family. Members of this family share a common methyl transferase function and are involved in the etiology of rare haploinsufficiency disorders. For each of the <i>KMT2</i> genes, at least one distinct disorder has been reported, yet clinical manifestations often overlap for multiple of these individually very rare disorders. Clinical care is currently focused on the management of symptoms with no targeted treatments available, illustrating a high unmet medical need and the urgency of developing disease-modifying therapeutic strategies. Antisense oligonucleotides (ASOs) are one option to treat some of these rare genetic disorders. ASOs are RNA-based treatments that can be employed to modulate gene expression through various mechanisms. In this work, we discuss the phenotypic features across the <i>KMT2</i>-associated NDDs and which ASO approaches are most suited for the treatment of each associated disorder. We hereby address variant-specific strategies as well as options applicable to larger groups of patients.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9933129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and Engineered U1 snRNA Rescue of Splicing Variants in a Turkish Neurodevelopmental Disease Cohort","authors":"Ece Sönmezler,&nbsp;Cristiana Stuani,&nbsp;Semra Hız Kurul,&nbsp;Serdal Güngör,&nbsp;Emanuele Buratti,&nbsp;Yavuz Oktay","doi":"10.1155/2024/7760556","DOIUrl":"https://doi.org/10.1155/2024/7760556","url":null,"abstract":"<div>\u0000 <p>Although they are rare in the population, rare neurodevelopmental disorders (RNDDs) constitute a significant portion of all rare diseases. While advancements in sequencing technologies led to improvements in diagnosing and managing rare neurodevelopmental diseases, accurate pathogenicity classification of the identified variants is still challenging. Sequence variants altering pre-mRNA splicing make up a significant part of pathogenic variants. Despite advances in the <i>in silico</i> prediction tools, noncanonical splice site variants are one of the groups of variants that pose a challenge in their clinical interpretation. In this study, we analyzed the effects of seven splicing variants we had previously proposed as disease-causing and demonstrated that all but one of the seven variants had a strong or moderate effect on splicing, as assessed by a minigene assay. Next, applying U1 snRNAs engineered for different splicing variants in the corresponding genes and expressed with minigene plasmids in HeLa cells provided a partial correction in four of the studied genes to varying degrees. Findings from our study highlight the importance of in vitro minigene-based assays for the reclassification of putative splice-altering variants of uncertain significance and the therapeutic potential of modified U1 snRNAs in RNDDs.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7760556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes—ENG and ACVRL1","authors":"Desiree DeMille,&nbsp;Jamie McDonald,&nbsp;Carmelo Bernabeu,&nbsp;Hilary Racher,&nbsp;Carla Olivieri,&nbsp;Claudia Cantarini,&nbsp;Anna Sbalchiero,&nbsp;Bryony A. Thompson,&nbsp;Luca Jovine,&nbsp;Claire L. Shovlin,&nbsp;Sophie Dupuis-Girod,&nbsp;Gaetan Lesca,&nbsp;Maud Tusseau,&nbsp;Arupa Ganguly,&nbsp;Raj S. Kasthuri,&nbsp;Jaime Jessen,&nbsp;Maarten P. G. Massink,&nbsp;Shoji Ichikawa,&nbsp;Pinar Bayrak-Toydemir","doi":"10.1155/2024/3043736","DOIUrl":"10.1155/2024/3043736","url":null,"abstract":"<div>\u0000 <p>The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the <i>ENG</i> and <i>ACVRL1</i> genes. Eight of the original ACMG/AMP rules were determined to not be applicable for <i>ENG</i>- or <i>ACVRL1</i>-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3043736","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141125031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple Sclerosis Polygenic Risk Is Not Enriched in Three Multicase Families in Comparison to Population-Based Cases","authors":"Ming Chen,&nbsp;Allan Motyer,&nbsp;Bruce V. Taylor,&nbsp;Bennet J. McComish,&nbsp;Kathryn P. Burdon,&nbsp;Jac C. Charlesworth,&nbsp;Nicholas B. Blackburn","doi":"10.1155/2024/9268911","DOIUrl":"10.1155/2024/9268911","url":null,"abstract":"<p>Multiple sclerosis (MS) is a complex neurological and autoimmune disease with an established genetic component. Families with multiple cases of MS are rare but do occur. We hypothesised that multicase families may have a heightened polygenic risk for MS. In this work, we have determined whether polygenic risk for MS is enriched in multicase families in comparison to a case-control cohort. Using the findings from the largest MS genome-wide association study, we calculated a weighted polygenic risk score (wPRS) for MS. We applied this wPRS to study a population-based MS case-control cohort (3,252 people with MS and 5,725 controls) and three multicase MS families (9 individuals with MS, 10 unaffected family members). For both the population-based cohort and the three families, 167 of the 233 known genome-wide significant MS-associated variants were identified and used to calculate the wPRS. Within the population-based cohort, the wPRS was significantly higher in MS cases than controls (<i>P</i> = 2.2 × 10⁻¹⁶). The wPRS of familial MS cases was not significantly different to population-based MS cases (<i>P</i> &gt; 0.05). Both affected and unaffected MS family members had higher wPRS than population controls. MS families have a higher polygenic risk for MS, but this did not differ to the polygenic risk of population-based MS cases. Only one family carried the established <i>HLA-DRB1 15:01</i> MS risk allele, which was present in both affected and unaffected family members. Across families, unaffected family members had an elevated polygenic risk in comparison to population controls indicating that a higher polygenic risk does not fully explain the clustering of MS in families.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140971522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAVaLRi: An Algorithm for Rapid Identification of Diagnostic Germline Variation","authors":"Robert J. Schuetz,&nbsp;Austin A. Antoniou,&nbsp;Grant E. Lammi,&nbsp;David M. Gordon,&nbsp;Harkness C. Kuck,&nbsp;Bimal P. Chaudhari,&nbsp;Peter White","doi":"10.1155/2024/6411444","DOIUrl":"https://doi.org/10.1155/2024/6411444","url":null,"abstract":"<p>Clinical exome and genome sequencing (ES/GS) have become indispensable diagnostic tools for rare genetic diseases (RGD). However, the interpretation of ES/GS presents a substantial operational challenge in clinical settings. Test interpretation requires the review of hundreds of genetic variants, a task that has become increasingly challenging given the rising use of ES/GS. In response, we present Clinical Assessment of Variants by Likelihood Ratios (CAVaLRi), which employ a modified likelihood ratio (LR) framework to assign diagnostic probabilities to candidate germline disease genes. CAVaLRi models aspects of the clinical variant assessment process, taking into consideration the predicted impact of the variant, the proband and parental genotypes, and the proband’s clinical characteristics. It also factors in computational phenotype noise and weighs the relative significance of genotype, phenotype, and variant segregation information. We trained and tested CAVaLRi on variant and phenotype data from an internal cohort of 655 clinical ES cases. For validation, CAVaLRi’s performance was benchmarked against four leading gene prioritization algorithms (Exomiser’s hiPHIVE and PhenIX prioritizers, LIRICAL, and XRare) using a distinct cohort of 12,832 ES cases. Our findings reveal that CAVaLRi significantly outperforms its counterparts when clinician-curated phenotype sets are used, as evidenced by its superior precision-recall curve (PR AUC: 0.701) and average diagnostic gene rank (1.59). Notably, even when substituting highly focused clinician-curated phenotype sets with large and potentially nonspecific computationally derived phenotypes, CAVaLRi retains its precision (PR AUC: 0.658; diagnostic gene average rank: 1.68) and markedly outperforms other tools. In a large, heterogeneous validation cohort, CAVaLRi stood out as the most precise prioritization algorithm (PR AUC: 0.335; average diagnostic rank: 1.91). In conclusion, CAVaLRi presents a robust solution for prioritizing diagnostic genes, surpassing current methods. It demonstrates resilience to noisy, computationally-derived phenotypes, providing a scalable strategy to help labs focus on the most diagnostically relevant variants, thus addressing the growing demand for ES/GS interpretation.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Association of Heterozygous p.R4810K of RNF213 and Long-Term Unfavorable Outcomes after Encephaloduroarteriosynangiosis in Chinese Pediatric Patients with Moyamoya Disease","authors":"Qingbao Guo,&nbsp;Fangbin Hao,&nbsp;Qian-Nan Wang,&nbsp;Jingjie Li,&nbsp;Shitong Liu,&nbsp;Zhengxing Zou,&nbsp;Simeng Liu,&nbsp;Xiaopeng Wang,&nbsp;Dan Yu,&nbsp;Gan Gao,&nbsp;Qian Zhang,&nbsp;Songtao Pei,&nbsp;Jie Feng,&nbsp;Rimiao Yang,&nbsp;Minjie Wang,&nbsp;Heguan Fu,&nbsp;Cong Han,&nbsp;Xiangyang Bao,&nbsp;Lian Duan","doi":"10.1155/2024/1844190","DOIUrl":"https://doi.org/10.1155/2024/1844190","url":null,"abstract":"&lt;p&gt;&lt;i&gt;Background&lt;/i&gt;. Previous studies have established that heterozygous mutation for the p.R4810K variant can influence the severity of the clinical phenotype in patients with moyamoya disease (MMD) at disease onset. However, the relationship between the p.R4810K variant and the clinical phenotype of long-term unfavorable outcomes in Chinese pediatric patients remains unclear. &lt;i&gt;Objectives&lt;/i&gt;. The primary aim of this study was to examine the association of heterozygous p.R4810K of RNF213 and long-term unfavorable outcomes after encephaloduroarteriosynangiosis (EDAS) in Chinese pediatric patients with MMD. &lt;i&gt;Method&lt;/i&gt;. In this retrospective cohort study, we included 259 pediatric patients with MMD who possessed the known p.R4810K genotype. These individuals underwent EDAS along with genotyping analysis for p.R4810K via a TaqMan probe and the QuantStudio 6 Flex Real-Time PCR System. Subsequently, we evaluated their long-term outcomes. The variables we assessed were age at diagnosis, gender, p.R4810K genotypes, initial modified Rankin scale (mRS), clinical manifestations (such as hemorrhage and ischemia), posterior cerebral artery (PCA) involvement combined with angiographic stage, and their history of risk factors like hyperlipidemia and hyperhomocysteinemia. Furthermore, we scrutinized long-term unfavorable outcomes using both univariate analyses and multivariate logistic regression to identify independent predictive factors. &lt;i&gt;Results&lt;/i&gt;. This study enrolled 259 Chinese pediatric patients with MMD, which included both newly and previously diagnosed cases, who underwent EDAS. The cohort comprised 130 male participants (50.19%) and 129 female participants (49.81%), with a median onset age of 8 years (median, IQR: 6-12 years). Among these patients, homozygous mutations were exceptionally rare, identified in only 4 individuals (1.54%), while the prevalence of heterozygous mutations was relatively higher, observed in 85 children (32.82%). The multivariate logistic regression showed that several factors were significantly associated with long-term unfavorable outcomes: older age at diagnosis (OR, 0.82 [95% CI, 0.7-0.96], &lt;i&gt;P&lt;/i&gt; = 0.014), onset with hematoma (OR, 12.76 [95% CI, 1.52-106.89], &lt;i&gt;P&lt;/i&gt; = 0.019), initial mRS (OR, 24.53 [95% CI, 6.51-92.41], &lt;i&gt;P&lt;/i&gt; &lt; 0.001), perioperative infarction (OR, 22.16 [95% CI, 1.45-337.96], &lt;i&gt;P&lt;/i&gt; = 0.026), and infarction during follow-up (OR, 14.5 [95% CI, 2.04-103.12], &lt;i&gt;P&lt;/i&gt; = 0.008). Furthermore, the cumulative incidence of initial infarction suggested that pediatric patients with homozygous or heterozygous mutations typically present at a younger age and exhibit a higher incidence of initial infarction compared to those carrying wild-type genotypes. &lt;i&gt;Conclusions&lt;/i&gt;. The study suggests that the p.R4810K variant is associated with the onset age of MMD in Chinese pediatric patients, potentially impacting long-term outcomes. Surprisingly low recurrent stroke rates were observed across all gen","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141164951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Single Diagnosis: Exploring Multidiagnostic Realities in Pediatric Patients through Genome Sequencing","authors":"Fen Guo,&nbsp;Ruby Liu,&nbsp;Yinghong Pan,&nbsp;Mary Colasanto,&nbsp;Christin Collins,&nbsp;Madhuri Hegde","doi":"10.1155/2024/9115364","DOIUrl":"10.1155/2024/9115364","url":null,"abstract":"<p>Recent advancements in the next-generation sequencing have illuminated the occurrence of multiple genetic diagnoses (MGD). While exome sequencing has provided insights, genome sequencing (GS), the most comprehensive diagnostic tool, remains underexplored for studying MGD prevalence. We retrospectively analyzed 1487 pediatric cases from our laboratory, employing GS to investigate the incidence of single definitive genetic diagnosis (SDD) and MGD in children suspected of having a genetic disease. Of these patients, 273 received at least one definitive diagnosis, including 245 with SDD (16.5%) and 28 with MGD (1.9%). Diagnostic yield was consistent across genders and unaffected by previous testing in SDD cases. Notably, prior testing significantly increased the diagnostic yield in MGD cases to 2.7% overall and 14.4% among diagnosed cases, compared to 1.1% for those with GS as a first-tier test. Age was a significant factor in diagnostic outcome for both SDD and MGD cases with neonates showing the highest diagnostic yield of 24.5% in SDD and a notably higher yield in MGD at 4.9%, representing 16.7% of the diagnosed cases. Of the 28 MGD cases, 17 exhibited distinct phenotypes, 9 had overlapping features, and 2 presented a mix, underscoring the genetic and phenotypic heterogeneity within this group. This study is the first to exclusively use GS to assess MGD prevalence. Our findings highlight the complexity of rare diseases and emphasize the importance of comprehensive, genome-level diagnostics. Clinicians must ensure that diagnoses fully account for the observed phenotypes to inform optimal therapeutic strategies and management.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}