Human Mutation最新文献

{"title":"Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)","authors":"Seda Susgun,&nbsp;Afif Ben-Mahmoud,&nbsp;Franz Rüschendorf,&nbsp;Bonsu Ku,&nbsp;Syeda Iqra Hussain,&nbsp;Solveig Schulz,&nbsp;Oliver Puk,&nbsp;Saskia Biskup,&nbsp;Jonathan D. J. Labonne,&nbsp;Dilan Wellalage Don,&nbsp;Vijay Gupta,&nbsp;Tae-Ik Choi,&nbsp;Saadullah Khan,&nbsp;Naveed Wasif,&nbsp;Yves Lacassie,&nbsp;Lawrence C. Layman,&nbsp;Sibel Aylin Ugur Iseri,&nbsp;Cheol-Hee Kim,&nbsp;Hyung-Goo Kim","doi":"10.1155/2024/5518289","DOIUrl":"10.1155/2024/5518289","url":null,"abstract":"<p>Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as <i>PIG</i> and <i>PGAP</i> genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. <i>PGAP2</i> stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in <i>PGAP2</i> in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with <i>PGAP2</i> variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with <i>PGAP2</i> variants.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381426","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":"Disruption of OVOL2 Distal Regulatory Elements as a Possible Mechanism Implicated in Corneal Endothelial Dystrophy","authors":"Lubica Dudakova,&nbsp;Lenka Noskova,&nbsp;Stanislav Kmoch,&nbsp;Martin Filipec,&nbsp;Ales Filous,&nbsp;Alice E. Davidson,&nbsp;Vasileios Toulis,&nbsp;Jana Jedlickova,&nbsp;Pavlina Skalicka,&nbsp;Hana Hartmannova,&nbsp;Viktor Stranecky,&nbsp;Jana Drabova,&nbsp;Drahuse Novotna,&nbsp;Marketa Havlovicova,&nbsp;Zdenek Sedlacek,&nbsp;Petra Liskova","doi":"10.1155/2024/4450082","DOIUrl":"10.1155/2024/4450082","url":null,"abstract":"<p>The genetic architecture of corneal endothelial dystrophies remains unknown in a substantial number of affected individuals. The proband investigated in the current study was diagnosed in the neonatal period with bilateral corneal opacification due to primary endothelial cell dysfunction. Neither his parents nor his sister had signs of corneal disease. Conventional karyotyping revealed a <i>de novo</i> translocation involving chromosomes 3 and 20, t(3;20)(q25;p11-12). Following genome and targeted Sanger sequencing analysis, the breakpoints were mapped at the nucleotide level. Notably, the breakpoint on chromosome 20 was identified to lie within the same topologically associated domain (TAD) as corneal endothelial dystrophy-associated gene <i>OVOL2</i>, and it is predicted to disrupt distal enhancers. The breakpoint at chromosome 3 is located within intron 2 of <i>PFN2</i>, which is currently not associated with any human disease. Further interrogation of the proband’s genome failed to identify any additional potentially pathogenic variants in corneal endothelial dystrophy-associated genes. Disruption of a candidate <i>cis</i>-regulatory element and/or positional effects induced by translocation of <i>OVOL2</i> to a novel genomic context may lead to an aberrant <i>OVOL2</i> expression, a previously characterized disease mechanism of corneal endothelial dystrophy. Further research is necessary to explore how disruption of regulatory elements may elucidate genetically unsolved corneal endothelial dystrophies.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386823","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":"Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG/AMP Framework","authors":"S. S. Cornelis, M. Bauwens, L. Haer-Wigman, M. De Bruyne, Madhulatha Pantrangi, E. De Baere, R. Hufnagel, C. Dhaenens, Frans P. M. Cremers","doi":"10.1155/2023/6815504","DOIUrl":"https://doi.org/10.1155/2023/6815504","url":null,"abstract":"Biallelic variants in ABCA4 cause Stargardt disease (STGD1), the most frequent heritable macular disease. Determination of the pathogenicity of variants in ABCA4 proves to be difficult due to (1) the high number of benign and pathogenic variants in the gene; (2) the presence of many rare ABCA4 variants; (3) the presence of complex alleles for which phasing data are absent; (4) the extensive variable expressivity of this disease and (5) reduced penetrance of hypomorphic variants. Therefore, the classification of many variants in ABCA4 is currently of uncertain significance. Here, we complemented the ABCA4 Leiden Open Variation Database (LOVD) with data from ~11,000 probands with ABCA4-associated inherited retinal diseases from literature up to the end of 2020. We carefully adapted the ACMG/AMP classifications to ABCA4 incorporating ClinGen recommendations and assigned these classifications to all 2,246 unique variants from the ABCA4 LOVD to increase the knowledge of pathogenicity. In total, 1,248 variants were categorized with a likely pathogenic or pathogenic classification, whereas 194 variants were categorized with a likely benign or benign classification. This uniform and improved structured reclassification, incorporating the largest dataset of ABCA4-associated retinopathy cases so far, will improve both the diagnosis as well as genetic counselling for individuals with ABCA4-associated retinopathy.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139155220","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":"Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes","authors":"Michael R. Fiorini, Allison A. Dilliott, Sali M. K. Farhan","doi":"10.1155/2023/8620557","DOIUrl":"https://doi.org/10.1155/2023/8620557","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease affecting approximately two per 100,000 individuals globally. While there are many benefits to offering early genetic testing to people with ALS, this has also led to an increase in the yield of novel variants of uncertain significance in ALS-associated genes. Computational (in silico) predictors, including REVEL and CADD, are widely employed to provide supporting evidence of pathogenicity for variants in conjunction with clinical, molecular, and other genetic evidence. However, in silico predictors are developed to be broadly applied across the human genome; thus, their ability to evaluate the consequences of variation in ALS-associated genes remains unclear. To resolve this ambiguity, we surveyed 20 definitive and moderate ClinGen-defined ALS-associated genes from two large, open-access ALS sequencing datasets (total people with <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\"> <mtext>ALS</mtext> <mo>=</mo> <mn>8,230</mn> </math> ; <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M2\"> <mtext>controls</mtext> <mo>=</mo> <mn>9,671</mn> </math> ) to investigate REVEL and CADD’s ability to predict which variants are most likely to be disease-causing in ALS. While our results indicate a predetermined pathogenicity threshold for REVEL that could be of clinical value for classifying variants in ALS-associated genes, an accurate threshold was not evident for CADD, and both in silico predictors were of limited value for resolving which variants of uncertain significance (VUS) may be likely pathogenic in ALS. Our findings allow us to provide important recommendations for the use of REVEL and CADD scores for variants and indicate that both tools should be used with caution when attempting to evaluate the pathogenicity of VUSs in ALS genetic testing.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136349044","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":"Evaluating the Utility of a New Pathogenicity Predictor for Pediatric Cardiomyopathy","authors":"Alyssa L. Rippert, Sarah Trackman, Danielle Burstein, J. William Gaynor, Heather Griffis, Christine Seymour, Rebecca Ahrens-Nicklas","doi":"10.1155/2023/8892833","DOIUrl":"https://doi.org/10.1155/2023/8892833","url":null,"abstract":"Pediatric cardiomyopathy (CM) has significant childhood morbidity and mortality which is caused by both genetic and environmental factors. Previous research has focused on identifying genetic variants in pediatric CM for diagnostic purposes, but not for risk stratification. The current study was modeled after previous work which showed an association between CardioBoost-classified disease-causing variants and an increased risk for severe clinical outcomes in adults with CM to assess if the same association is true in pediatric CM. This was a retrospective, single-center cohort study that evaluated outcomes in pediatric CM patients who were evaluated by the Children’s Hospital of Philadelphia (CHOP). CardioBoost (CB) scores were generated for these patients, and scores were categorized as ≤0.1, 0.1-0.9, and ≥0.9. Composite endpoint was freedom from a major adverse cardiac event (MACE). 104 patients were included in the final analysis. 32 (31%) had DCM, 45 (43%) had HCM, and 27 (26%) had other CM. There was no significant association between CB score and clinical outcome in pediatric CM patients. Overall, this study highlights the continued deficits in variant interpretation for pediatric CM. We recommend using caution when applying this tool to stratify clinical outcomes in the pediatric population.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136233996","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":"Clinical SMN1 and SMN2 Gene-Specific Sequencing to Enhance the Clinical Sensitivity of Spinal Muscular Atrophy Diagnostic Testing","authors":"Cecelia R. Miller, Jin Fang, Pamela Snyder, Susan E. Long, Thomas W. Prior, Dan Jones, Matthew R. Avenarius","doi":"10.1155/2023/6436853","DOIUrl":"https://doi.org/10.1155/2023/6436853","url":null,"abstract":"Purpose. Therapeutic advances in the treatment of spinal muscular atrophy (SMA) prompt the need for robust and efficient molecular diagnosis of this disease. Approximately five percent of SMA cases are attributable to one copy of SMN1 with a hypomorphic or inactivating variant in trans with a deleted or converted allele. These intragenic variants are challenging to definitively localize to SMN1 due to its sequence homology with the SMN2 gene. To enhance the clinical sensitivity of SMA diagnostic testing, we present an optimized gene-specific sequencing assay to localize variants to either SMN1 or SMN2. Methods. SMN1 and SMN2 genes are independently amplified by long-range allele-specific PCR. Long-range products are used in subsequent nested PCR reactions to amplify the coding exons of SMN1 and SMN2. The resulting products are sequenced using standard Sanger-based methodologies and analyzed for disease-associated alterations. Results. 83 probands suspicious for a clinical diagnosis of SMA with a nondiagnostic SMN dosage result were sequenced for intragenic variants in the SMN1 gene. Gene-specific sequencing revealed likely disease-associated variants in SMN1 in 42 cases (50.6%). Of the 42 variants, 27 are unique including 16 loss-of-function variants, 9 missense variants, 1 in-frame deletion variant, and 1 splice site variant. Conclusions. Herein, we describe an optimized assay for clinical sequencing of the full coding region of SMN1 and SMN2. This assay uses standard techniques and equipment readily available to most molecular diagnostic laboratories.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135728878","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":"Long-Read Sequencing Identified a Large Novel δ/β-Globin Gene Deletion in a Chinese Family","authors":"Jianlong Zhuang, Yu Zheng, Yuying Jiang, Junyu Wang, Shuhong Zeng, Nansong Liu","doi":"10.1155/2023/2766625","DOIUrl":"https://doi.org/10.1155/2023/2766625","url":null,"abstract":"Objective. Increasingly rare thalassemia has been identified with the advanced use of long-read sequencing based on long-read technology. Here, we aim to present a novel δ/β-globin gene deletion identified by long-read sequencing technology. Methods. Enrolled in this study was a family from the Quanzhou region of Southeast China. Routine blood analysis and hemoglobin (Hb) capillary electrophoresis were used for hematological screening. Genetic testing for common α- and β-thalassemia was carried out using the reverse dot blot hybridization technique. Long-read sequencing was performed to detect rare globin gene variants. Specific gap-polymerase chain reaction (gap-PCR) and/or Sanger sequencing were further used to verify the detected variants. Results. None of the common α- and β-thalassemia mutations or deletions were observed in the family. However, decreased levels of MCV, MCH, and abnormal Hb bands were observed in the family members, who were suspected as rare thalassemia carriers. Further, long-read sequencing demonstrated a large novel 7.414 kb deletion NG_000007.3:g.63511_70924del partially cover HBB and HBD globin genes causing delta-beta fusion gene in the proband. Parental verification indicated that the deletion was inherited from the proband’s father, while none of the globin gene variants were observed in the proband’s mother. In addition, the novel δ/β-globin gene deletion was further verified by gap-PCR and Sanger sequencing. Conclusion. In this study, we first present a large novel δ/β-globin gene deletion in a Chinese family using long-read sequencing, which may cause δβ-thalassemia. This study further enhances that long-read sequencing would be applied as a sharp tool for detecting rare and novel globin gene variants.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135549970","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":"A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2","authors":"Maria Zanti, Denise G. O'Mahony, Michael T. Parsons, Hongyan Li, Joe Dennis, Kristiina Aittomäkkiki, Irene L. Andrulis, Hoda Anton-Culver, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Melissa A. Brown, Saundra S. Buys, Federico Canzian, Sandrine M. Caputo, Jose E. Castelao, Jenny Chang-Claude, None GC-HBOC study Collaborators, Kamila Czene, Mary B. Daly, Arcangela De Nicolo, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Aleksandra Gentry-Maharaj, Willemina R. R. Geurts - Giele, Graham G. Giles, Gord Glendon, Mark S. Goldberg, Encarna B. Gómez Garcia, Melanie Güendert, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Frans B. L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Claude Houdayer, Richard S. Houlston, Anthony Howell, None ABCTB Investigators, Milena Jakimovska, Anna Jakubowska, Helena Jernström, Esther M. John, Rudolf Kaaks, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, James V. Lacey, Diether Lambrechts, Melanie Léoné, Annika Lindblom, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Usha Menon, Roger L. Milne, Alvaro N. Monteiro, Rachel A. Murphy, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Kenneth Offit, Sue K. Park, Paul James, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Kevin Punie, Paolo Radice, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Efraim H. Rosenberg, Emmanouil Saloustros, Dale P. Sandler, Marjanka K. Schmidt, Rita K. Schmutzler, Xiao-Ou Shu","doi":"10.1155/2023/9961341","DOIUrl":"https://doi.org/10.1155/2023/9961341","url":null,"abstract":"A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135553037","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":"Genotype and Phenotype Characteristics of Chinese Pediatric Patients with Primary Hyperoxaluria","authors":"Yucheng Ge, Yukun Liu, Ruichao Zhan, Zhenqiang Zhao, Jun Li, Wenying Wang, Ye Tian","doi":"10.1155/2023/4875680","DOIUrl":"https://doi.org/10.1155/2023/4875680","url":null,"abstract":"Primary hyperoxaluria (PH) is a rare monogenic disorder characterized by recurrent kidney stones, nephrocalcinosis, and renal impairment. To study the genotype and phenotype characteristics, we evaluated the clinical data of 42 Chinese pediatric PH patients who were diagnosed from May 2016 to April 2022. We found that patients with the PH3 type showed an earlier age of onset than those with the PH1 and PH2 types (1 versus 5 and 8 years, respectively, <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\"> <mi>P</mi> <mo><</mo> <mn>0.001</mn> </math> ). Urine citrate was significantly lower in PH1 and PH2 patients than that in PH3 patients (91.81 and 85.56 versus 163.9 μg/mg, respectively, <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M2\"> <mi>P</mi> <mo>=</mo> <mn>0.044</mn> </math> ). Spot urine oxalate levels were slightly higher in PH1 than that in PH2 and PH3 patients (457.9 versus 182.38 and 309.14 μg/mg, respectively, <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M3\"> <mi>P</mi> <mo>=</mo> <mn>0.189</mn> </math> ). A significant negative correlation between the urine calcium/creatinine ratio and the oxalate/creatinine ratio was observed in the entire PH cohort ( <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M4\"> <mi>r</mi> <mo>=</mo> <mo>−</mo> <mn>0.360</mn> </math> , <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M5\"> <mi>P</mi> <mo>=</mo> <mn>0.04</mn> </math> ) and the PH3 cohort ( <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M6\"> <mi>r</mi> <mo>=</mo> <mo>−</mo> <mn>0.674</mn> </math> , <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M7\"> <mi>P</mi> <mo>=</mo> <mn>0.003</mn> </math> ). PH-causative genes showed hotspot mutations or regions, including c.815_816insGA and c.33dup in AGXT, 864_865del in GRHPR, and exon 6 skipping and c.769T>G in HOGA1. In the PH1 cohort, the estimated glomerular filtration rate (eGFR) was lowest in patients with heterozygous c.33dup. In the PH3 cohort, patients with heterozygous exon 6 skipping presented the lowest eGFR and a significant decrease in the renal survival advantage. In summary, PH1 patients exhibit much more severe phenotypes than those with other types. Hotspot mutations or regions exist in patients with all types of PH and show differences among ethnicities. Genotype-phenotype correlations are observed in PH1 and PH3.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134912511","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":"Combination of Synonymous and Missense Mutations in JAK3 Gene Contributes to Severe Combined Immunodeficiency in One Child","authors":"Xingcui Wang, Rujin Tian, Haozheng Zhang, Mohnad Abdalla, Lu Bai, Yuqiang Lv, Min Gao, Guiyu Lin, Qinghua Liu, Yi Liu, Qiuxia He, Dong Wang, Kaihui Zhang","doi":"10.1155/2023/6633251","DOIUrl":"https://doi.org/10.1155/2023/6633251","url":null,"abstract":"Janus kinase 3 (JAK3, NP_000206.2) is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction JAK/STAT pathway. JAK3 gene variants can lead to autosomal recessive severe combined immunodeficiency (SCID), which is T-cell-negative, B-cell-positive, and NK-cell-negative (OMIM: 600802). We have detected one infant suffering from cytomegalovirus, fever, and impaired respiratory function with low lymphocytes and immunoglobulin. Two compound heterozygous variants, c.1914G&gt;T (p.L638=) and c.1048C&gt;T (p.R350W), were identified in the proband, each of which was inherited from one unaffected parent. Analysis of splicing was carried out by the Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay which both showed a deletion of exon 14 (128 bp) resulting from the c.1914G&gt;T variant at the mRNA level. Bioinformatic analysis for the reported c.1048C&gt;T (p.R350W) 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 finally have diagnosed the infant as SCID (OMIM: 600802). The study is the first study regarding a synonymous variant of JAK3 gene influencing alternative splicing. Our findings expand the mutation spectrum leading to JAK3 deficiency-related diseases and provide exact information for genetic counseling.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135690439","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}