Human Mutation最新文献

{"title":"Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review","authors":"Jun Kido,&nbsp;Keishin Sugawara,&nbsp;Sotiria Tavoulari,&nbsp;Georgios Makris,&nbsp;Véronique Rüfenacht,&nbsp;Kimitoshi Nakamura,&nbsp;Edmund R. S. Kunji,&nbsp;Johannes Häberle","doi":"10.1155/humu/9326326","DOIUrl":"https://doi.org/10.1155/humu/9326326","url":null,"abstract":"<p>Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in <i>SLC25A13</i>. The disease presents with age-dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult-onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to “adolescent and adult citrin deficiency,” AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post-NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G&gt;A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (&lt; -2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain <i>SLC25A13</i> genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post-NICCD cases and 49% (20/41) of AACD patients.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9326326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856908","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":"Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666 PDGFRB Variants and Their Role in Downstream Signaling","authors":"Titas Gladkauskas,&nbsp;Ileana Cristea,&nbsp;Roya Mehrasa,&nbsp;Jean-Baptiste Demoulin,&nbsp;Bjørn Tore Gjertsen,&nbsp;Ove Bruland,&nbsp;Eyvind Rødahl,&nbsp;Cecilie Bredrup","doi":"10.1155/humu/6664372","DOIUrl":"https://doi.org/10.1155/humu/6664372","url":null,"abstract":"<p>Four different amino acid substitutions have been reported at the p.Asn666 position in platelet-derived growth factor receptor <i>β</i> (PDGFR<i>β</i>): p.Asn666Lys, p.Asn666Tyr, p.Asn666Ser, and p.Asn666His. All four substitutions result in strikingly different phenotypes, ranging from somatic infantile myofibromatosis in p.Asn666Lys and ocular pterygium–digital keloid dysplasia in p.Asn666Tyr to a severe form of Penttinen syndrome in p.Asn666Ser, while p.Asn666His is associated with a complex phenotype characterized by debilitating hand and foot contractures and facial coarseness. Here, we show that the p.Asn666Lys, p.Asn666Tyr, and p.Asn666His substitutions result in increased total PDGFR<i>β</i> phosphorylation at 32°C compared to 37°C. All four substitutions exhibit distinct activation patterns of specific PDGFR<i>β</i> tyrosine residues at both temperatures, indicating a unique activation of each variant. The temperature effect on downstream signaling is present across all substitutions, resulting in substitution-specific downstream signaling at both 37°C and 32°C. This complex interplay of downstream signaling proteins could be important for the clinical manifestations of p.Asn666 <i>PDGFRB</i> variants. Furthermore, variant-specific overactivation of tyrosine residues and downstream signaling at 32°C emphasize the importance of temperature as an environmental factor in the pathogenesis of this diverse group of disorders.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6664372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856823","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":"Exploring Monogenic, Polygenic, and Epigenetic Models of Common Variable Immunodeficiency","authors":"Tayebeh Ranjbarnejad,&nbsp;Hassan Abolhassani,&nbsp;Roya Sherkat,&nbsp;Mansoor Salehi,&nbsp;Fatemeh Ranjbarnejad,&nbsp;Nasimeh Vatandoost,&nbsp;Mohammadreza Sharifi","doi":"10.1155/humu/1725906","DOIUrl":"https://doi.org/10.1155/humu/1725906","url":null,"abstract":"<p>Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID is genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found in a low percentage of patients, and multifactorial or polygenic inheritance may be involved in unsolved patients. In the complex disease model, the epistatic effect of multiple variants in several genes and environmental factors such as infections may contribute. Epigenetic modifications, such as DNA methylation changes, are also proposed to be involved in CVID pathogenesis. In general, the pathogenic mechanism and molecular basis of CVID disease are still unknown, and identifying patterns of association across the genome in polygenic models and epigenetic modification profiles in CVID requires more studies. Here, we describe the current knowledge of the molecular genetic basis of CVID from monogenic, polygenic, and epigenetic aspects.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1725906","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836089","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":"Intron Variant Cause DICER1 Syndrome With Pleuropulmonary Blastoma","authors":"Rujin Tian,&nbsp;Yixiao Li,&nbsp;Lin Zhong,&nbsp;Haozheng Zhang,&nbsp;Zhongtao Gai,&nbsp;Dong Wang,&nbsp;Li Song,&nbsp;Kaihui Zhang","doi":"10.1155/humu/8884636","DOIUrl":"https://doi.org/10.1155/humu/8884636","url":null,"abstract":"<p><i>DICER1</i> syndrome (OMIM 601200) is a rare autosomal dominant familial tumor susceptibility disorder with heterozygous <i>DICER1</i> germline mutations. The most common tumor in clinical practice is pleuropulmonary blastoma. Pleuropulmonary blastoma is a rare pediatric lung tumor that begins during fetal lung development and is part of an inherited tumor syndrome. We found a patient with pleuropulmonary blastoma in clinical practice and performed whole-exome testing on him and his parents. The mutation is located at <i>DICER1</i> gene, c. 1510-16G&gt;A. The tested person has a heterozygous variation at this locus. The tested person’s father has no variation at this locus, while the tested person’s mother has a heterozygous variation at this locus. According to the ACMG guidelines, this mutation has been preliminarily determined as clinically significant (uncertain) PM2_Supporting: The frequency of this supporting variation in the normal population database is unknown; there is no report of correlation for this locus in the literature database, and the ClinVar database does not feature this locus. In point pathogenicity analysis results, analysis of splicing was carried out by Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay, both of which showed a deletion of exon 10 resulting from the c. 1510-16G&gt;A variant at the mRNA level. Bioinformatic analysis of the reported c. 1510-16G&gt;A variant suggests that the variant is pathogenic. Based on the clinical characteristics of the patient and the functional verification of the gene variants, our pediatricians have finally diagnosed the infant with pleuropulmonary blastoma (OMIM 601200). Our findings expand the mutation spectrum leading to <i>DICER1</i> deficiency-related diseases and provide accurate information for genetic counseling.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8884636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749700","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":"Splicing Analysis of Exonic TSC1 and TSC2 Gene Variants Causing Tuberous Sclerosis Complex","authors":"Qingqing You,&nbsp;Jingwei Liu,&nbsp;Ran Zhang,&nbsp;Zhi Wang,&nbsp;Bingying Zhang,&nbsp;Wencong Guo,&nbsp;Ning Xu,&nbsp;Irene Bottillo,&nbsp;Leping Shao","doi":"10.1155/humu/1497712","DOIUrl":"https://doi.org/10.1155/humu/1497712","url":null,"abstract":"<p>Tuberous sclerosis complex (TSC) is characterized by abnormalities in cell proliferation and migration, leading to the development of hamartomas, benign tumors, or malignant cancers, affecting both the skin and brain, as well as potentially impacting the heart, kidneys, lungs, and eyes, with varying patterns of involvement over a lifetime. It is primarily caused by mutations in the TSC1 and TSC2 genes. Aberrant splicing is a crucial factor in hereditary diseases. Alternative splicing is a key mechanism for expanding the diversity of the human proteome. Mutations disrupting canonical splice sites or splicing regulatory elements impede the utilization of splice sites, leading to exon skipping and intron retention. We comprehensively analyzed missense and nonsense mutations of TSC1 and TSC2 genes using bioinformatics tools and identified 10 candidate mutations affecting pre-mRNA splicing through minigene analysis. Mutations in TSC genes can lead to partial or complete exon skipping and/or intron retention through complex mechanisms. This study emphasizes the importance of evaluating their roles in the splicing of suspected pathogenic variants in TSC.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1497712","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741314","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":"Variants in CAPN3 Causing Autosomal Dominant Limb–Girdle Muscular Dystrophy Combined With Calpain-3 Deficiency","authors":"Thomas Krag,&nbsp;Emily Nasho,&nbsp;Lauren Brady,&nbsp;Camille Verebi,&nbsp;France Leturcq,&nbsp;Edoardo Malfatti,&nbsp;Morten Duno,&nbsp;Mark Tarnopolsky,&nbsp;John Vissing","doi":"10.1155/humu/9301465","DOIUrl":"https://doi.org/10.1155/humu/9301465","url":null,"abstract":"<p><b>Abstract:</b> Limb–girdle muscular dystrophy Type 2A/R1 or calpain-3 deficiency is the most common autosomal recessive limb–girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain-3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain-3 gene in mildly to moderately affected patients with limb–girdle muscular dystrophy without biallelic gene variants in <i>CAPN3</i>. Here, we report four cases with creatine kinase levels above 1500 U/L, mild-to-moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the <i>CAPN3</i> variant c.304C&gt;T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in <i>CAPN3</i>. The third and fourth patients were heterozygous for c.1371C&gt;G; p.(Asn457Lys) and c.1490C&gt;T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near-complete loss of calpain-3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild-to-moderate proximal weakness, increased level of creatine kinase, and near-complete loss of calpain-3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain-3. This information could aid in determining whether a <i>CAPN3</i> variant of unknown significance is pathological.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9301465","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726852","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":"Detection of Pathogenic Intronic Variants for COL4A5 Gene in X-Linked Alport Syndrome: Developing a Novel Methodology","authors":"Yixiao Li,&nbsp;Rujin Tian,&nbsp;Yu Hei,&nbsp;Haozheng Zhang,&nbsp;Yanan Yang,&nbsp;Yuqiang Lv,&nbsp;Weiran Zhou,&nbsp;Qingwei Guo,&nbsp;Beibei Niu,&nbsp;Kaisheng Li,&nbsp;Dong Wang,&nbsp;Hongmei Xin,&nbsp;Kaihui Zhang","doi":"10.1155/humu/1443580","DOIUrl":"https://doi.org/10.1155/humu/1443580","url":null,"abstract":"<p><i>COL4A5</i> gene variants could result in the X-linked Alport syndrome 1, dominant inheritance (XLAS1) (Online Mendelian Inheritance in Man (OMIM) #301050). The splicing changes can be identified through targeted RNA sequencing (RNA seq), but obtaining accessible patient samples from urine cells and skin fibroblasts is challenging. Moreover, extracted <i>COL4A5</i> transcripts cannot be amplified due to their nonexpression in peripheral blood mononuclear cells (PBMCs). In the study, we induced patient-derived PBMCs to differentiate into induced pluripotent stem cells (iPSCs) and lymphoblasts (using phytohemagglutinin (PHA)). Through cDNA Sanger sequencing, we identified the true pathogenicity of two <i>cis</i>-intron variants of the <i>COL4A5</i> gene in lymphoblasts and iPSCs. Furthermore, the results were also verified by minigene assay in vitro. Through RNA seq and real-time PCR, we further confirmed that the expression level of <i>COL4A5</i> in lymphoblasts is sufficient for Sanger sequencing to detect splicing changes. In conclusion, we have devised a straightforward, cost-effective, noninvasive, and robust method for detecting abnormal transcripts resulting from pathogenic variants in the <i>COL4A5</i> gene. Furthermore, this method is equally suitable for genes that are expressed in lymphoblasts but not in PBMCs. Finally, splicing changes account for a relatively high proportion of patients with XLAS who were overlooked through routine whole-exome sequencing (WES), and the c.4822-12T&gt;C variant may become a target for specific antisense oligonucleotide therapies.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1443580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581850","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":"Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability","authors":"Amélie Cordovado,&nbsp;Yvan Hérenger,&nbsp;Coline Cormier,&nbsp;Estrella López-Martín,&nbsp;Hannah Stamberger,&nbsp;Laurence Faivre,&nbsp;Anne-Sophie Denommé-Pichon,&nbsp;Antonio Vitobello,&nbsp;Hamza Hadj Abdallah,&nbsp;Giulia Barcia,&nbsp;Thomas Courtin,&nbsp;Beatriz Martínez-Delgado,&nbsp;Eva Bermejo-Sánchez,&nbsp;María J. Barrero,&nbsp;Brooklynn Gasser,&nbsp;Stéphane Bezieau,&nbsp;Sébastien Küry,&nbsp;Sarah Weckhuysen,&nbsp;Frédéric Laumonnier,&nbsp;Annick Toutain,&nbsp;Marie-Laure Vuillaume","doi":"10.1155/humu/7085599","DOIUrl":"https://doi.org/10.1155/humu/7085599","url":null,"abstract":"<p>Intellectual disability is a neurodevelopmental disorder, affecting 2%–3% of the population, with a genetic cause in the majority of cases. <i>ATP9A</i> (Online Mendelian Inheritance in Man (OMIM) ^∗609126, NM_006045.3) has recently been added to the list of candidate genes involved in this disorder with the identification of biallelic truncating variants in patients with a neurodevelopmental disorder. In this study, we propose a novel mode of inheritance for <i>ATP9A</i>-related disorders with the identification of five de novo heterozygous missense variants (p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)), in patients with intellectual disability. In a patient with a similar phenotype, we also identified two truncating variants in <i>ATP9A</i> (p.(Arg145 ^∗), p.(Glu901 ^∗)), adding a novel family to the six already described in the literature with the recessive mode of inheritance. Functional studies were performed to assess the pathogenicity of these variants. Overexpression of four selected missense mutant forms of <i>Atp9a</i> in HeLa cells and in primary neuronal cultures led to a loss of mature dendritic spines. In HeLa cells, the endosomal localization of the protein encoded by three of these missense variants was preserved whereas the fourth remained blocked in the endoplasmic reticulum. To mimic the effect on neuronal morphology and spine density of nonsense variants, small hairpin RNAs (shRNAs) were used. They induced a decreased expression of <i>ATP9A</i>, affecting the neuronal arborization by decreasing the number of dendrites per neuron. Our results therefore demonstrate the pathogenicity of <i>ATP9A</i> heterozygous missense variants and confirm the role of <i>ATP9A</i> in neuronal maturation and in brain wiring during development. They strengthen the association of <i>ATP9A</i> with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for <i>ATP9A</i>-related disorders.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7085599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554306","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":"Genome Sequencing of Rare Disease Patients Through the Korean Regional Rare Disease Diagnostic Support Program","authors":"Rin Khang,&nbsp;Hane Lee,&nbsp;Jihye Kim,&nbsp;Dongseok Moon,&nbsp;Seokhui Jang,&nbsp;Eugene Lee,&nbsp;Yongjun Song,&nbsp;Seung Woo Ryu,&nbsp;Sohyun Lee,&nbsp;Heonjong Han,&nbsp;Sukwon Kim,&nbsp;Sohyun Jang,&nbsp;Young Bae Sohn,&nbsp;Won Seop Kim,&nbsp;Ji-Eun Lee,&nbsp;Juwon Kim,&nbsp;Yonggon Cho,&nbsp;Bo Lyun Lee,&nbsp;Han Hyuk Lim,&nbsp;Hoon Kook,&nbsp;Ki-Soo Kang,&nbsp;Soonhak Kwon,&nbsp;Jiwon Lee,&nbsp;Go Hun Seo,&nbsp;Seung Hwan Oh,&nbsp;Chong Kun Cheon","doi":"10.1155/humu/6096758","DOIUrl":"https://doi.org/10.1155/humu/6096758","url":null,"abstract":"<p>Affecting fewer than 20,000 people as defined in South Korea, rare diseases pose significant diagnostic challenges due to their diverse manifestations and genetic heterogeneity. Genome sequencing (GS) offers a promising solution by enabling simultaneous screening for thousands of rare genetic disorders. This study explores the diagnostic utility and necessity of GS within the government-funded Korean Regional Rare Disease Diagnostic Support Program (KR-RDSP), a collaborative initiative involving 11 regional rare disease centers across Korea. The program was launched as a proof-of-concept study in 2023 to equip the genetic clinics with a diagnostic tool to expedite the diagnoses for rare disease patients who reside outside the urban Seoul region where diagnostic resources are limited. The study leveraged GS to diagnose a cohort of 400 patients exhibiting a wide spectrum of symptoms. The overall diagnostic yield was 36.3% (145/400), with 4.8% (7/145) of the diagnosed patients being reported with variants that could not have been identified by chromosomal microarray or exome sequencing (ES), highlighting the added value of comprehensive genomic analysis. The implementation of a centralized GS analysis system streamlined the diagnostic process, enabling timely reporting within a reasonable turnaround time of ≤ 35 days. Segregation analysis by Sanger sequencing played a crucial role in confirming or reclassifying variant pathogenicity by elucidating inheritance patterns. Here, we summarize diagnostic statistics from the 400 GS dataset gathered from June 2023 to December 2023 and show interesting and informative case examples that illustrate the diagnostic efficacy of GS, highlighting its ability to uncover elusive genetic etiologies and provide personalized treatment insights. The study also highlights the successful implementation of the program for the 11 regional rare disease centers across Korea with a practical workflow, comprehensive testing, comparable diagnostic yield to previous reports, and, most importantly, reasonable turnaround time.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6096758","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513838","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":"Gene Mutation Characteristics and Prognostic Significance in Acute Myeloid Leukemia Patients From Northeast China","authors":"Yiyang Shen,&nbsp;Shuang Fu,&nbsp;Xuan Liu,&nbsp;Jianing Liu,&nbsp;Yu Fu,&nbsp;Yue Zhao,&nbsp;Xinxin Wang,&nbsp;Xujian Jiang,&nbsp;Jihong Zhang","doi":"10.1155/humu/7730186","DOIUrl":"https://doi.org/10.1155/humu/7730186","url":null,"abstract":"<p>A great part of studies on the correlation between gene mutations and prognosis in acute myeloid leukemia (AML) patients are based on Western populations. To profile the genomic landscape of AML patients in Northeast China, we retrospectively analyzed the clinical data of 377 newly diagnosed AML patients in Shengjing Hospital of China Medical University from 2016 to 2022 and compared them with data from other populations with different genetic backgrounds. The mutation status of <i>NPM1</i>, <i>FLT3-ITD</i>, <i>FLT3-TKD</i>, <i>CEBPA</i> (CCAT enhancer binding protein alpha), <i>ASXL1</i>, <i>TET2</i>, <i>KIT</i>, <i>DNMT3A</i> (DNA methyltransferase 3A), <i>IDH1</i>, <i>IDH2</i>, <i>EZH2</i> (enhancer of zeste 2), <i>RUNX1</i>, <i>TP53</i>, <i>NRAS</i>, and <i>GATA2</i> was acquired by next-generation sequencing (NGS) technology; meanwhile, the clinical data of the patients were collected. The Cox regression model was used to analyze factors affecting patient survival and the impact of <i>CEBPA</i> and <i>DNMT3A</i> mutation on prognosis, and the results were different from those in other populations. Seventy-seven of 377 patients (20.4%) were detected with <i>CEBPA</i> mutations, which was higher than the 2%–6% in the Caucasian population. In the <i>CEBPA^dm</i> patients who did not receive bone marrow transplantation, the prognosis of male patients (<i>n</i> = 18) was significantly better than that of female patients (<i>n</i> = 21) (<i>p</i> = 0.0242). Sixty-three of 377 patients (16.7%) carried the <i>DNMT3A</i> mutation, which was lower than the mutation frequency of 20.9% in the German–Austrian population, and the prognosis of these patients was significantly poorer (<i>p</i> = 0.0052). In addition, the prognostic evaluation value of the <i>DNMT3A</i> mutation in AML patients was not affected regardless of the presence of the <i>NPM1</i> and <i>FLT3-ITD</i> comutation (<i>p</i> &gt; 0.05), nor the mutation site of <i>DNMT3A</i>. In conclusion, for the Northeastern Chinese population, the prognosis of male patients with <i>CEBPA^dm</i> was more favorable than that of female patients, and the <i>DNMT3A</i> mutation serves as an independent predictor of poor prognosis in AML. These results highlighted the central role of genetic background in precision medicine strategies and further emphasized the importance of the clinical characteristics of AML gene mutations in the Chinese population.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7730186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447040","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}