Application of Clinical Genetics最新文献

{"title":"Association of Y Chromosome Microdeletions with Reproductive Profiles in 2010 Infertile Male Patients in China.","authors":"Gangxin Chen, Pengyu Huang, Haiyan Li, Beihong Zheng, Yan Sun","doi":"10.2147/TACG.S560740","DOIUrl":"10.2147/TACG.S560740","url":null,"abstract":"<p><strong>Objective: </strong>To analyze the incidence of different types of Y chromosome microdeletions in infertile male patients in China, and to investigate the relationship between microdeletions in different azoospermia factor (AZF) regions and sperm kinetic parameters, sperm morphological parameters, and sex hormone levels.</p><p><strong>Methods: </strong>A total of 2010 infertile male patients who visited the Fujian Provincial Maternity and Child Health Hospital from 2022 to 2025 were selected. Their Y chromosome microdeletions (YCMD), semen routine, sperm morphology, sperm DNA fragmentation index (DFI), and sex hormone levels were detected, and the relationships between these parameters were analyzed.</p><p><strong>Results: </strong>The incidence of Y chromosome microdeletions in patients was 8.66% (174/2010). Among the 174 patients with AZF microdeletions, the proportion of AZFc region deletions was 85.63% (149/174), AZFa region deletions accounted for 2.30% (4/174), AZFb/c region deletions accounted for 8.05% (14/174), AZFa/b/c region deletions accounted for 2.87% (5/174), and heterochromosome deletions accounted for 1.15% (2/174). There were no statistically significant differences in semen volume, testosterone (T), and prolactin (PRL) levels between patients with different types of AZF deletions and the normal group (P>0.05). There were statistically significant differences in sperm concentration, progressive motility (PR), non-progressive motility (NP), total sperm motility, normal sperm morphology rate, sperm DFI, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) between patients with different types of AZF deletions and the normal group (P<0.05).</p><p><strong>Conclusion: </strong>AZFc deletion is the most common type of Y chromosome microdeletion in infertile male patients in China. Patients with AZFa and AZFa/b/c combined deletions often present with azoospermia. AZFc deletion is associated with abnormal sperm quality parameters and disordered hormone levels.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"275-282"},"PeriodicalIF":2.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Partial Monosomy 21q Due to De Novo t(15;21)(q26.3;q22.11): A Case Report with Clinical and Molecular Findings.","authors":"Somayeh Takrim Nojehdeh, Tannaz Fattahi, Sara Arish, Haleh Mokabber, Ramiz Nobakht, Sana Davarnia, Behzad Davarnia","doi":"10.2147/TACG.S542614","DOIUrl":"10.2147/TACG.S542614","url":null,"abstract":"<p><strong>Background: </strong>Partial monosomy of chromosome 21q is a rare genetic disorder characterized by a wide spectrum of clinical manifestations including intellectual disability, developmental delay, and distinctive craniofacial features. Concurrent deletions involving chromosome 15q26 are also infrequent and typically benign.</p><p><strong>Objective: </strong>This study reports a rare case of de novo unbalanced translocation between chromosomes 15q26.3 and 21q22.11, resulting in partial monosomy 21q and a benign deletion of 15q26.3, highlighting the importance of comprehensive cytogenetic and molecular analysis.</p><p><strong>Methods: </strong>Peripheral blood samples from the proband and her parents were analyzed using GTG-banding karyotype, fluorescence in situ hybridization (FISH), and whole-genome oligo-array comparative genomic hybridization (array CGH).</p><p><strong>Results: </strong>The proband, a 36-year-old woman with intellectual disability and developmental delay, exhibited a karyotype of 45,XX,der(15)t(15;21)(q26.3;q22.11),-21. Array CGH revealed a 17.32 Mb deletion at 21q11.2q22.11 encompassing 37 genes, and a benign 673 kb deletion at 15q26.3 involving 13 genes. Clinical features included multiple craniofacial dysmorphisms, low birth weight, short stature, and dental anomalies.</p><p><strong>Conclusion: </strong>This case represents the first reported instance from Iran of a pathogenic partial monosomy 21q due to an unbalanced translocation with chromosome 15q26.3. The findings underscore the critical role of integrated cytogenetic and molecular diagnostics in identifying complex chromosomal rearrangements and contribute to the understanding of genotype-phenotype correlations in partial monosomy 21q.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"267-274"},"PeriodicalIF":2.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prognostic Value of Integrating Copy Number Alteration Profiles in <i>NPM1</i>-Mutated Acute Myeloid Leukemia: An Exploratory Study.","authors":"Chunxia Zhang, Li Gao, Ming Gong, Chundi Liu, Dongmei Zhang, Zhenling Li","doi":"10.2147/TACG.S559124","DOIUrl":"10.2147/TACG.S559124","url":null,"abstract":"<p><strong>Background: </strong>Characteristic genetic events underpin acute myeloid leukemia (AML) heterogeneity and enable precise risk stratification. However, prognostic assessment remains ambiguous in many patients due to inadequate integration of specific genetic information.</p><p><strong>Materials and methods: </strong>Eighty <i>NPM1</i>-mutated AML patients were enrolled. Copy number alterations (CNAs) were detected via shallow whole-genome sequencing (sWGS), and concurrent mutations via targeted deep sequencing of myeloid malignancy-associated genes. Clinical and laboratory parameters were integrated with genomic data for statistical analysis, with the aim of assessing the potential clinical significance of CNA profiles in prognostic stratification.</p><p><strong>Results: </strong><i>NPM1</i> mutation subtypes A, B, and D were the most prevalent, with all patients harboring at least two concurrent mutations (4-5 mutations being the most frequent), and these mutations commonly co-occurred with those in <i>FLT3, DNMT3A, TET2, IDH2</i>, and <i>NRAS</i>. Forty-one samples (51%) exhibited CNAs across diverse genomic regions, with dup(18)(p11.23) identified as the most recurrent locus. No significant differences in FAB classification, hematologic parameters, demographic characteristics (gender, age), co-mutation profiles, complete remission (CR) rates, or survival outcomes were observed between the CNA-positive and CNA-negative groups. Univariate survival analysis revealed patients with ≥2 CNAs, or <i>FLT3</i>-internal tandem duplication (<i>FLT3</i>-ITD) had significantly shorter overall survival (OS). Notably, integrative analysis of CNAs with mutational profiles showed that patients harboring both <i>FLT3</i>-ITD and ≥2 CNAs had the poorest OS, followed by those with <i>FLT3</i>-ITD and <2 CNAs, and multivariate Cox regression analysis suggests a potential association between ≥3 CNAs and adverse outcomes; however, given the limited sample size of cases with high CNA burden, this result should be interpreted with caution.</p><p><strong>Conclusion: </strong>This exploratory study suggests that combining CNAs and gene mutation profiles may potentially improve the existing prognostic evaluation system for <i>NPM1</i>-mutated AML patients. Confirmation of these results requires additional validation in larger prospective cohorts.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"251-266"},"PeriodicalIF":2.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12685752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stepwise Diagnostic Strategy Integrating Long-Read Sequencing for the Interpretation of Phenotype-Genotype Discordance in Dystrophinopathy.","authors":"Qingyue Yuan, Chang Liu, Yanyu Lu, Xu Han, Zhaoxia Wang, Yun Yuan, Zhiying Xie","doi":"10.2147/TACG.S544691","DOIUrl":"10.2147/TACG.S544691","url":null,"abstract":"<p><strong>Introduction: </strong>Pathogenic variants in the <i>DMD</i> gene maintaining the open reading frame typically cause Becker muscular dystrophy. Here, we report a 7.7-year-old boy exhibiting a severe Duchenne muscular dystrophy phenotype, despite an in-frame deletion of <i>DMD</i> exons 50-51 identified by initial genetic testing, representing a notable exception to the conventional reading-frame rule.</p><p><strong>Methods: </strong>To elucidate his phenotype-genotype discordance, muscle biopsy and subsequent dystrophin protein and mRNA analyses were conducted, followed by long-read sequencing of <i>DMD</i> gene and splicing analysis.</p><p><strong>Results: </strong>Muscle biopsy revealed a dystrophic pattern and negative expression of dystrophin-N and dystrophin-C. The <i>dystrophin</i> mRNA analysis identified two out-of-frame <i>DMD</i> transcripts, which were different from the in-frame deletion of <i>DMD</i> exons 50-51 and can explain his severe phenotype. Long-read sequencing uncovered a novel deletion variant (~97kb) in <i>DMD</i> gene, which produced the two out-of-frame transcripts through aberrant splicing.</p><p><strong>Conclusion: </strong>This case underscores the necessity of a stepwise molecular analysis strategy for the interpretation of phenotype-genotype discordance in dystrophinopathy. This stepwise diagnostic approach is essential for accurately characterizing <i>DMD</i> variants, guiding patient management, and genetic counseling.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"243-249"},"PeriodicalIF":2.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145670278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Masked Thalassemia: A Rare Case of a Patient with Normal HbA2 Levels, β-Thalassemia Pathogenic Variant (CD39 C>T), and a Novel δ-Globin Gene Deletion.","authors":"Massimiliano Chetta, Annamaria Salamandra, Marina Tarsitano, Marcella D'Antonio, Elvira Sannino, Serena Torre, Carmina Fatigati, Silvia Costantini, Paola D'Ambrosio, Manuela Priolo, Paolo Ricchi","doi":"10.2147/TACG.S544633","DOIUrl":"10.2147/TACG.S544633","url":null,"abstract":"<p><p>Thalassemia is a group of inherited blood disorders caused by defects in hemoglobin production, the protein that transports oxygen in red blood cells. These diseases are characterized by either diminished or missing production of one of the globin chains, which are often the alpha or beta chains that comprise hemoglobin. Diagnosis is based on a combination of laboratory tests, including hemoglobin electrophoresis, globin chain chromatography, and genetic analysis. However, diagnosis can become challenging when typical hematological features of thalassemia are not matched by expected biochemical findings. One such situation occurs when HbA2 levels appear normal despite a suspected β-thalassemia trait. This can happen when a β-globin gene variant is present alongside a δ-globin gene pathogenic variant, producing an atypical profile that may mask the true diagnosis. In this case report, we describe a patient carrying a heterozygous β-globin pathogenic variant (<i>HBB</i> c.118C>T; p.Gln40Ter, also known as codon 39) coexisting with a large novel 1.6 kb deletion in the delta-globin gene (<i>HBD</i>) that removes the first two exons. We discuss the diagnostic challenges and clinical implications associated with this rare genetic combination, emphasizing the critical role of comprehensive molecular testing in accurately identifying complex thalassemia cases. This report contributes to the literature by documenting a novel δ-globin deletion in combination with a β-thalassemia variant, providing valuable insights for clinicians and geneticists in the interpretation and management of atypical thalassemia profiles.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"233-241"},"PeriodicalIF":2.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12620583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Invasive Prenatal Testing in the Kingdom of Saudi Arabia: Current Status of Adoption and Roadmap for the Future.","authors":"Majid Alfadhel, Amal AlHashem, Wesam Kurdi, Maha Tulbah, Saleh AlGamdi, Mohammed Almannai, Iman AlAmoudi, Mariam M AlEissa, Nada AlAgil, Soha Tashkandi, Nancy Awad, Rita Ojeil","doi":"10.2147/TACG.S535206","DOIUrl":"10.2147/TACG.S535206","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive prenatal testing (NIPT) has emerged as a significant advancement in prenatal screening that offers safer and more accurate detection of chromosomal abnormalities compared to conventional methods. The study aimed to evaluate the status of NIPT adoption in the Kingdom of Saudi Arabia (KSA).</p><p><strong>Methods: </strong>A comprehensive 3-phased study was conducted to examine the status of NIPT in KSA. In Phase I targeted literature review was conducted followed by Phase II and Phase III which involved qualitative interview-based exploration with key stakeholders and round table discussion with key opinion leaders, respectively.</p><p><strong>Results: </strong>Key stakeholders in KSA underscore NIPT's clinical value and economic benefits while addressing coverage disparities and the push for national guidelines. In KSA, NIPT prescription is influenced by multiple factors such as logistics, personnel, cost, accessibility, policy, and validation. Addressing these factors is important for the widespread adoption of NIPT as a primary screening test. Key opinion leaders suggest that accurate infrastructure, multidisciplinary care, patient education, and expansion of NIPT's scope are crucial. To address current challenges, proactive collaboration of both public and private sectors is essential. NIPT usage has increased in KSA over time. It has now been recommended for all pregnant women, leading to an increase in demand for national guidelines to regulate the practice along with awareness campaigns about the value of testing.</p><p><strong>Conclusion: </strong>A structured, phased roadmap for implementing NIPT in Saudi Arabia is crucial to ensure cost-effectiveness, cultural and ethical appropriateness, and nationwide access for all pregnant women.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"219-231"},"PeriodicalIF":2.6,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12577452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intragenic <i>TTN</i> Deletions in a Single Family with Dilated Cardiomyopathy.","authors":"Marketa Wayhelova, Petra Peldova, Alice Krebsova, Michaela Nemcikova, Matej Sojka, Milan Macek","doi":"10.2147/TACG.S550190","DOIUrl":"10.2147/TACG.S550190","url":null,"abstract":"<p><p>The <i>TTN</i> gene (MIM:188840) encodes titin, the largest human protein with exclusive expression in the cardiac and skeletal muscles. Rare variants disrupting the <i>TTN</i> gene are frequent causes of dilated cardiomyopathy and several forms of skeletal myopathy. We report a unique occurrence of two novel, distinct but overlapping intragenic <i>TTN</i> deletions in multiple relatives from a single Czech family with the clinical manifestation of dilated cardiomyopathy (DCM). After clinical exome sequencing using the custom virtual gene panel, two distinct deletions affecting the <i>TTN</i> gene (NM_001267550.2) were detected. The first deletion (3.599 kb in length) encompasses five exons with the breakpoints in exons 326 and 330. The longer one (4.859 kb in length) disrupts exon 326 only. Both deletions segregate with the cardiomyopathy phenotype, and none of the tested individuals carry both. The familial segregation of two distinct intragenic <i>TTN</i> deletions extends the broad spectrum of rare variants in the pathogenesis of DCM. The presence of severely affected carriers of the reported DNA variants and obligatory healthy non-carriers raises the debate on their ancestral origin. Our data demonstrate the clinical benefits of the family cascade screening and molecular genetic analysis in familial DCM, enabling early and effective multidisciplinary medical care.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"211-217"},"PeriodicalIF":2.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145349125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial 3M Syndrome - as an Example of Diagnostic Difficulties in Rare Genetic Syndromes.","authors":"Magdalena Pasińska, Joanna M Rusecka, Agnieszka Sobczyńska-Tomaszewska, Maciej Pasiński","doi":"10.2147/TACG.S535270","DOIUrl":"10.2147/TACG.S535270","url":null,"abstract":"<p><strong>Introduction: </strong>A lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities.</p><p><strong>Methods: </strong>Whole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0.</p><p><strong>Results: </strong>This article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the <i>CUL7</i> gene.</p><p><strong>Discussion: </strong>This is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient's clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"199-210"},"PeriodicalIF":2.6,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exome Sequencing Analysis and Clinical Features of a Chinese Patient with 3M Syndrome and A Review of Literature.","authors":"Xiao-Li Chen, Dai-Shan Zheng, Yi-Fan Shen, Zhen-Lang Lin, Shang-Qin Chen, Xiu-Man Xiao","doi":"10.2147/TACG.S538739","DOIUrl":"10.2147/TACG.S538739","url":null,"abstract":"<p><strong>Background: </strong>3M syndrome is a rare autosomal recessive genetic disorder characterized by significant intrauterine and postnatal growth restriction. There is limited research on its genetic basis within the Chinese population.</p><p><strong>Methods: </strong>We performed trio-based whole-exome sequencing to identify the pathogenic gene in the affected child and collected and organized clinical and imaging data. Relevant information was reviewed through a literature search.</p><p><strong>Results: </strong>In this study, we present a case involving prenatal diagnostic abnormalities and postnatal confirmation of 3M syndrome, including detailed documentation of clinical features and associated genetic variants. Notably, during prenatal ultrasound examination, the fetus exhibited increased nuchal translucency (NT) and delayed limb development. Postnatally, whole-exome sequencing revealed the compound heterozygous mutations in the CUL7 gene: c.3646-2A>G and c.3355+5G>A. The splicing mutation c.3646-2A>G is a novel pathogenic mutation, while the c.3355+5G>A mutation has been previously reported. In-silico analysis predicted strong pathogenicity for both splicing mutations. Through follow-up, we observed that the patient's height and weight are below the first percentile, with abnormal skeletal development and distinctive facial features. Based on literature review of reported cases, these mutations disrupt the normal function of CUL7-OBSL1-CCDC8 complex in the ubiquitin-proteasome pathway, leading to impaired growth regulation.</p><p><strong>Discussion: </strong>This study identified a novel splicing mutation in the CUL7 gene in a patient with 3M syndrome, expanding the genetic spectrum of this disorder and contributing novel insights for clinical diagnosis and management.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"189-197"},"PeriodicalIF":2.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12499243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemizygous <i>IL2RG</i> Variants Impair IL-2-Induced STAT5 Phosphorylation and Transcriptional Activity Causing X-Linked Severe Combined Immunodeficiency.","authors":"Ning Zhang, Yi-Lin Sang, Wu Zhu, Yu-Rong Wang, Yan-Yan Yu, Ya-Hui Chen, Juan Du, Wen-Bin He, Yue-Qiu Tan, Fu-Yan Wang","doi":"10.2147/TACG.S525027","DOIUrl":"10.2147/TACG.S525027","url":null,"abstract":"<p><strong>Purpose: </strong>X-linked severe combined immunodeficiency (X-SCID) is an inherited immune disorder caused by pathogenic variants in the <i>IL2RG</i> gene, leading to recurrent infections. Identifying these variants and elucidating their pathogenic mechanisms are crucial for precise diagnosis and treatment, prenatal diagnosis, and preimplantation genetic testing (PGT). This study aimed to identify candidate variants in four families with suspected immunodeficiency, assess their pathogenicity, elucidate their pathogenic mechanisms, and provide a basis for precise treatment, prenatal diagnosis, and PGT.</p><p><strong>Patients and methods: </strong>Four families with suspected immunodeficiency were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Whole exome sequencing (WES) was used to identify the genetic etiology. Functional experiments were performed to assess the pathogenicity of the identified <i>IL2RG</i> variants, and to elucidate their pathogenic mechanisms.</p><p><strong>Results: </strong>WES identified four <i>IL2RG</i> variants: three hemizygous (c.569G>C:p.R190P, c.515T>C:p.L172P, c.217A>C:p.T73P) and one heterozygous (c.1091C>T:p.T364I) variants. Three of these variants were novel. Initially three variants (p.R190P, p.T73P, and p.T364I) were classified as variants of uncertain significance (VUS) and one (p.L172P) was likely pathogenic (LP) according to ACMG/AMP guidelines. Functional analyses revealed reduced STAT5 phosphorylation and transcriptional activity across all variants, supporting the reclassification of three variants (p.R190P, p.L172P, and p.T73P) as likely pathogenic (LP), and one variant (p.T364I) as VUS with a Bayesian score of 5. Furthermore, IP-MS analysis revealed that the mutant IL2RG resulted in reduced cell-surface expression and abnormal nuclear localization. Therefore, the identified <i>IL2RG</i> variants impair IL-2-induced STAT5 phosphorylation and transcriptional activity to cause X-linked severe combined immunodeficiency in these families.</p><p><strong>Conclusion: </strong>This study highlights the critical role of functional analysis in clarifying variant pathogenicity and provides a clear example of pathogenicity assessment for <i>IL2RG</i> variants. Integrating genomic and functional data enhance diagnostic precision and informs precise treatment strategies, genetic counseling, prenatal diagnosis, and PGT for X-SCID.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"18 ","pages":"175-187"},"PeriodicalIF":2.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}