Human Mutation最新文献

{"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":"64 3","pages":"0"},"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":"18 1","pages":"0"},"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":"84 1","pages":"0"},"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":"213 1","pages":"0"},"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":"26 1","pages":"0"},"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":"63 1","pages":"0"},"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}

{"title":"The UCMD-Causing COL6A1 (<math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\">\u0000 <mi>c</mi>\u0000 <mo>.</mo>\u0000 <mn>930</mn>\u0000 <mo>+</mo>\u0000 <mn>189</mn>\u0000 <mi>C</mi>\u0000 ","authors":"C. Freiburg, Herimela Solomon-Degefa, Patrick Freiburg, Matthias Mörgelin, Véronique Bolduc, Sebastian Schmitz, Pierpaolo Ala, Francesco Muntoni, E. Behrmann, Carsten G. Bönnemann, A. Schiavinato, Mats Paulsson, R. Wagener","doi":"10.1155/2023/6892763","DOIUrl":"https://doi.org/10.1155/2023/6892763","url":null,"abstract":"Collagen VI is a unique member of the collagen family. Its assembly is a complex multistep process and the vulnerability of the process is manifested in muscular diseases. Mutations in COL6A1, COL6A2, and COL6A3 lead to the severe Ullrich Congenital Muscular Dystrophy (UCMD) and a spectrum of disease of varying severity including the milder Bethlem muscular dystrophy. The recently identified dominant intronic mutation in COL6A1 (\u0000 \u0000 c\u0000 .\u0000 930\u0000 +\u0000 189\u0000 C\u0000 >\u0000 T\u0000 \u0000 ) leads to the partial in-frame insertion of a pseudoexon between exon 11 and exon 12. The pseudoexon is translated into 24 amino acid residues in the N-terminal region of the triple helix and results in the interruption of the typical G-X-Y motif. This recurrent de novo mutation leads to UCMD with a severe progression within the first decade of life. Here, we demonstrate that a mutation-specific antibody detects the mutant chain colocalizing with wild type collagen VI in the endomysium in patient muscle. Surprisingly, in the cell culture of patient dermal fibroblasts, the mutant chain is secreted as a single α chain, while in parallel, normal collagen VI tetramers are assembled with the wild-type α1 chain. The mutant chain cannot be incorporated into collagen VI tetramers but forms large aggregates in the extracellular matrix that may retain the ability to interact with collagen VI and potentially with other molecules. Also, α1 chain-deficient WI-26 VA4 cells transfected with the mutant α1 chain do not assemble collagen VI tetramers but, instead, form aggregates. Interestingly, both the wild type and the mutant single α1 chains form amorphous aggregates when expressed in HEK293 cells in the absence of α2 and α3 chains. The detection of aggregated, assembly incompetent, mutant collagen VI α1 chains provides novel insights into the disease pathophysiology of UCMD patients with the COL6A1 (\u0000 \u0000 c\u0000 .\u0000 930\u0000 +\u0000 189\u0000 C\u0000 >\u0000 T\u0000 \u0000 ) mutation.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43551312","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":"Evaluation in Monogenic Diabetes of the Impact of GCK, HNF1A, and HNF4A Variants on Splicing through the Combined Use of In Silico Tools and Minigene Assays","authors":"D. Bouvet, A. Blondel, Jean-Madeleine de Sainte Agathe, G. Leroy, C. Saint-Martin, C. Bellanné-Chantelot","doi":"10.1155/2023/6661013","DOIUrl":"https://doi.org/10.1155/2023/6661013","url":null,"abstract":"Variants in GCK, HNF1A, and HNF4A genes are the three main causes of monogenic diabetes. Determining the molecular etiology is essential for patients with monogenic diabetes to benefit from the most appropriate treatment. The increasing number of variants of unknown significance (VUS) is a major issue in genetic diagnosis, and assessing the impact of variants on RNA splicing is challenging, particularly for genes expressed in tissues not easily accessible as in monogenic diabetes. The in vitro functional splicing assay based on a minigene construct is an appropriate approach. Here, we performed in silico analysis using SpliceAI and SPiP and prioritized 36 spliceogenic variants in GCK, HNF1A, and HNF4A. Predictions were secondarily compared with Pangolin and AbSplice-DNA bioinformatics tools which include tissue-specific annotations. We assessed the effect of selected variants on RNA splicing using minigene assays. These assays validated splicing defects for 33 out of 36 spliceogenic variants consisting of exon skipping (15%), exonic deletions (18%), intronic retentions (24%), and complex splicing patterns (42%). This provided additional evidence to reclassify 23 out of 31 (74%) VUS including missense, synonymous, and intronic noncanonical splice site variants as likely pathogenic variants. Comparison of in silico analysis with minigene results showed the robustness of bioinformatics tools to prioritize spliceogenic variants, but revealed inconsistencies in the location of cryptic splice sites underlying the importance of confirming predicted splicing alterations with functional splicing assays. Our study underlines the feasibility and the benefits of implementing minigene-splicing assays in the genetic testing of monogenic diabetes after a prior in-depth in silico analysis.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49033606","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":"Early-Onset Aortic Dissection: Characterization of a New Pathogenic Splicing Variation in the MYH11 Gene with Several In-Frame Abnormal Transcripts","authors":"P. Arnaud, Margaux Cadenet, Zakaria Mougin, C. Le Goff, S. Perbet, Mathilde Francois, S. Dupuis-Girod, C. Boileau, N. Hanna","doi":"10.1155/2023/1410230","DOIUrl":"https://doi.org/10.1155/2023/1410230","url":null,"abstract":"Rare pathogenic variants in the MYH11 gene are responsible for thoracic aortic aneurysms and dissections. They are usually heterozygous missense variants or in-frame deletions of several amino acids without alteration of the reading frame and mainly affect the coiled-coil domain of the protein. Variants leading to a premature stop codon have been described in patients with another phenotype, megacystis-microcolon-intestinal hypoperistalsis syndrome, with an autosomal recessive inheritance. The physiopathological mechanisms arising from the different genetic alterations affecting the MYH11 gene are still poorly understood. Consequently, variants of unknown significance are relatively frequent in this gene. We have identified a variant affecting the consensus donor splice site of exon 29 in the MYH11 gene in a patient who suddenly died from an aortic type A dissection at the age of 23 years old. A transcript analysis on cultured fibroblasts has highlighted several abnormal transcripts including two in-frame transcripts. The first one is a deletion of the last 78 nucleotides of exon 29, corresponding to the use of a cryptic alternative donor splice site; the second one corresponds to an exon 29 skipping. Familial screening has revealed that this molecular event occurred de novo in the proband. Taken together, these experiments allowed us to classify this variant as pathogenic. This case underlines the challenging aspect of the discovery of variations in the MYH11 gene for which the consequences on splicing should be systematically studied in detail.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49534373","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":"Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy","authors":"Aurélie Gouronc, Elodie Javey, Anne-Sophie Leuvrey, Elsa Nourisson, Sylvie Friedmann, Valérie Reichert, N. Derive, C. Francannet, B. Keren, J. Lévy, M. Planes, L. Ruaud, J. Amiel, H. Dollfus, Sophie Scheidecker, J. Muller","doi":"10.1155/2023/2564200","DOIUrl":"https://doi.org/10.1155/2023/2564200","url":null,"abstract":"Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a de novo pathogenic variant in trans of an inherited pathogenic variant. These two genetic mechanisms are expected to be extremely rare, and few data are available in the literature, especially regarding ciliopathies. In this study, we investigated 940 individuals (812 families) with a suspected ciliopathy by Sanger sequencing, high-throughput sequencing and/or SNP array analysis and performed a literature review of UPD and de novo variants in ciliopathies. In a large cohort of 623 individuals (511 families) with a molecular diagnosis of ciliopathy (mainly Bardet-Biedl syndrome and Alström syndrome), we identified five UPD, revealing an inherited pathogenic variant and five pathogenic variants of de novo appearance (in trans of another pathogenic variant). Moreover, from these ten cases, we reported 15 different pathogenic variants of which five are novel. We demonstrated a relatively high prevalence of UPD and de novo variants in a large cohort of ciliopathies and highlighted the importance of identifying such rare genetic events, especially for genetic counseling.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"1 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64792931","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}