Human Mutation最新文献

{"title":"Reasons and Resolutions for Inconsistent Variant Interpretation","authors":"Liling Lin,&nbsp;Hong Pan,&nbsp;Yu Qi,&nbsp;Yinan Ma,&nbsp;Ling Qiu","doi":"10.1155/2023/4955235","DOIUrl":"10.1155/2023/4955235","url":null,"abstract":"<div>\u0000 <p>In the postgenomic era, variant interpretation is crucial for diagnosing monogenic diseases, which is the premise of precision medicine. The bottleneck and difficulty of genetic disease diagnosis have switched from the inaccessibility of detection technology to the interpretation of sequencing results. Multiple studies have suggested that the inconsistency rate of interlaboratory variant interpretation is approximately 10~40%. However, many clinicians have not paid enough attention to this area at present. In this review, we summarized the reasons for inconsistency, including classification methodology, information obtained by the interpreter, evidence application, and expert judgement. For clinicians, genetic counsellors, and molecular pathologists, it is necessary to reevaluate genetic reports, especially those supported by old literature and databases in clinical practice. For unresolvable cases, pedigree analysis, collaboration with research labs for functional experiments, and long-term follow-up to combine advanced clinical presentations with updated data and literature are needed.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4955235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48122300","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":"The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots","authors":"Grégory Lazarian,&nbsp;Bernard Leroy,&nbsp;Floriane Theves,&nbsp;Myriam Hormi,&nbsp;Rémi Letestu,&nbsp;Virginie Eclache,&nbsp;Giulia Tueur,&nbsp;Adam Ameur,&nbsp;Audrey Bidet,&nbsp;Pascale Cornillet-Lefebvre,&nbsp;Frédéric Davi,&nbsp;Eric Delabesse,&nbsp;Marie-Hélène Estienne,&nbsp;Pascaline Etancelin,&nbsp;Olivier Kosmider,&nbsp;Sophy Laibe,&nbsp;Marc Muller,&nbsp;Nathalie Nadal,&nbsp;Dina Naguib,&nbsp;Cédric Pastoret,&nbsp;Stéphanie Poulain,&nbsp;Pierre Sujobert,&nbsp;Lauren Veronese,&nbsp;Samia Imache,&nbsp;Valérie Lefebvre,&nbsp;Florence Cymbalista,&nbsp;Fanny Baran-Marszak,&nbsp;Thierry Soussi,&nbsp;French Innovative Leukemia Organization (FILO)","doi":"10.1155/2023/4880113","DOIUrl":"10.1155/2023/4880113","url":null,"abstract":"<div>\u0000 <p><i>TP53</i> aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal <i>TP53</i> abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of <i>TP53</i> variants in CLL, 1,056 <i>TP53</i> variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 <i>TP53</i> variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by <i>TP53</i> to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of <i>TP53</i> status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple <i>TP53</i> variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed <i>TP53</i> mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4880113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44964736","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":"Somatic Double Inactivation of NF1 Associated with NF1-Related Pectus Excavatum Deformity","authors":"Cristina Chelleri,&nbsp;Marcello Scala,&nbsp;Patrizia De Marco,&nbsp;Vittorio Guerriero,&nbsp;Marzia Ognibene,&nbsp;Francesca Madia,&nbsp;Sara Guerrisi,&nbsp;Marco Di Duca,&nbsp;Michele Torre,&nbsp;Serena Tamburro,&nbsp;Paolo Scudieri,&nbsp;Gianluca Piccolo,&nbsp;Girolamo Mattioli,&nbsp;Francesca Buffelli,&nbsp;Paolo Uva,&nbsp;Diego Vozzi,&nbsp;Ezio Fulcheri,&nbsp;Pasquale Striano,&nbsp;Maria Cristina Diana,&nbsp;Federico Zara","doi":"10.1155/2023/3160653","DOIUrl":"10.1155/2023/3160653","url":null,"abstract":"<div>\u0000 <p>Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder with a broad spectrum of associated signs and symptoms, including skeletal anomalies. The association of NF1 with anterior chest wall deformities has been recently reported, especially the pectus excavatum (PE). Over the years, several authors have suggested loss of heterozygosity (LOH) as the possible pathogenic mechanism underlying the development of the typical NF1 skeletal features. Here, we report a NF1 patient with severe chest deformity and harboring the germline heterozygous pathogenic <i>NF1</i> variant NM_001042492.3: c.4271delC p.(Ala1424Glufs ^∗4). Through next-generation sequencing (NGS), we investigated the affected cartilage from the PE deformity and identified the additional frameshift variant NM_001042492.3: c.2953delC p.(Gln985Lysfs ^∗7), occurring as a somatic NF1 second hit mutation. Exome sequencing confirmed the absence of additional variants of potential pathogenic relevance. Western blot analysis showed the absence of wild-type NF1 protein in the cartilage of the patient, consistent with a somatic double inactivation (SDI) of <i>NF1</i>. Taken together, our findings support the role of SDI in NF1-related PE, widening the spectrum of the pathophysiological mechanisms involved in NF1-related skeletal features.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/3160653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41471934","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":"Quantitative Phenotype Morbidity Description of SATB2-Associated Syndrome","authors":"Yuri A. Zarate,&nbsp;Katherine Bosanko,&nbsp;Amrit Kannan,&nbsp;Ashlen Thomason,&nbsp;Beth Nutt,&nbsp;Nihit Kumar,&nbsp;Kirt Simmons,&nbsp;Aaron Hiegert,&nbsp;Larry Hartzell,&nbsp;Adam Johnson,&nbsp;Tabitha Prater,&nbsp;Eduardo Pérez-Palma,&nbsp;Tobias Brünger,&nbsp;Arthur Stefanski,&nbsp;Dennis Lal,&nbsp;Aisling R. Caffrey","doi":"10.1155/2023/8200176","DOIUrl":"10.1155/2023/8200176","url":null,"abstract":"<div>\u0000 <p>Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, <i>SATB2</i>-associated syndrome (SAS) is caused by pathogenic variants in <i>SATB2</i>. The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features. Higher (more severe) systemic and total (sum of neurodevelopmental and systemic scores) scores were seen for null variants located after amino acid 350 (the start of the CUT1 domain), the recurrent missense Arg389Cys variant (<i>n</i> = 10), intragenic deletions, and larger chromosomal deletions. The Arg389Cys variant had the highest cognitive, verbal, and sialorrhea severity scores, while large chromosomal deletions had the highest expressive, ambulation, palate, feeding and growth, neurodevelopmental, and total scores. Missense variants not located in the CUT1 or CUT2 domain scored lower in several subcategories. We conclude that the SAS severity score allows quantitative phenotype morbidity description that can be used in routine clinical counseling. Further refinement and validation of the SAS severity score are expected over time. All data from this project can be interactively explored in a new portal.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/8200176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48139339","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":"A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency","authors":"Alistair T. Pagnamenta,&nbsp;Jing Yu,&nbsp;Tracey A. Willis,&nbsp;Mona Hashim,&nbsp;Eleanor G. Seaby,&nbsp;Susan Walker,&nbsp;Jiaqi Xian,&nbsp;Emily W. Y. Cheng,&nbsp;Ana Lisa Taylor Tavares,&nbsp;Francesca Forzano,&nbsp;Helen Cox,&nbsp;Tabib Dabir,&nbsp;Angela F. Brady,&nbsp;Neeti Ghali,&nbsp;Santosh S. Atanur,&nbsp;Sarah Ennis,&nbsp;Diana Baralle,&nbsp;Jenny C. Taylor","doi":"10.1155/2023/6633248","DOIUrl":"10.1155/2023/6633248","url":null,"abstract":"<div>\u0000 <p><i>SRRM2</i> encodes a splicing factor recently implicated in developmental disorders due to a statistical enrichment of de novo mutations. Using data from the 100,000 Genomes Project, four unrelated individuals with intellectual disability (ID) were identified, each harbouring de novo whole gene deletions of <i>SRRM2</i>. Deletions ranged between 248 and 482 kb in size and all distal breakpoints clustered within a complex 144 kb palindrome situated 75 kb upstream of <i>SRRM2.</i> Strikingly, three of the deletions were complex, with inverted internal segments of 45-94 kb. In one proband-mother duo, de novo status was inferred by haplotype analysis. Together with two additional patients who harboured smaller predicted protein-truncating variants (p.Arg632 ^∗ and p.Ala2223Leufs ^∗13), we estimate the prevalence of this condition in cohorts of patients with unexplained ID to be ~1/1300. Phenotypic blending, present for two cases with additional pathogenic variants in <i>CASR/PKD1</i> and <i>SLC17A5</i>, hampered the phenotypic delineation of this recently described condition. Our data highlights the benefits of genome sequencing for resolving structural complexity and inferring de novo status. The genomic architecture of 16p13.3 may give rise to relatively high rates of complex rearrangements, adding to the list of loci associated with recurrent genomic disorders.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6633248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46162624","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":"A Novel Alu Element Insertion in ATM Induces Exon Skipping in Suspected HBOC Patients","authors":"Janin Klein,&nbsp;Aldrige B. Allister,&nbsp;Gunnar Schmidt,&nbsp;Annette Otto,&nbsp;Kai Heinecke,&nbsp;Jördis Bax-Knoche,&nbsp;Carmela Beger,&nbsp;Sarah Becker,&nbsp;Stephan Bartels,&nbsp;Tim Ripperger,&nbsp;Jens Bohne,&nbsp;Thilo Dörk,&nbsp;Brigitte Schlegelberger,&nbsp;Winfried Hofmann,&nbsp;Doris Steinemann","doi":"10.1155/2023/6623515","DOIUrl":"10.1155/2023/6623515","url":null,"abstract":"<div>\u0000 <p>The vast majority of patients at risk of hereditary breast and/or ovarian cancer (HBOC) syndrome remain without a molecular diagnosis after routine genetic testing. One type of genomic alteration that is commonly missed by diagnostic pipelines is mobile element insertions (MEIs). Here, we reanalyzed multigene panel data from suspected HBOC patients using the MEI detection tool <i>Mobster</i>. A novel <i>Alu</i> element insertion in <i>ATM</i> intron 54 (ATM:c.8010+30_8010+31insAluYa5) was identified as a potential contributing factor in seven patients. Transcript analysis of patient-derived RNA from three heterozygous carriers revealed exon 54 skipping in 38% of total <i>ATM</i> transcripts. To manifest the direct association between the <i>Alu</i> element insertion and the aberrant splice pattern, HEK293T and MCF7 cells were transfected with wild-type or <i>Alu</i> element-carrying minigene constructs. On average, 77% of plasmid-derived transcripts lacked exon 54 in the presence of the <i>Alu</i> element insertion compared to only 4.7% of transcripts expressed by the wild-type minigene. These results strongly suggest ATM:c.8010+30_8010+31insAluYa5 as the main driver of <i>ATM</i> exon 54 skipping. Since this exon loss is predicted to cause a frameshift and a premature stop codon, mutant transcripts are unlikely to translate into functional proteins. Based on its estimated frequency of up to 0.05% in control populations, we propose to consider ATM:c.8010+30_8010+31insAluYa5 in suspected HBOC patients and to clarify its role in carcinogenesis through future epidemiological and functional analyses. Generally, the implementation of MEI detection tools in diagnostic sequencing pipelines could increase the diagnostic yield, as MEIs are likely underestimated contributors to genetic diseases.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6623515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48220679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation","authors":"Jessica N. Hatton,&nbsp;Megan N. Frone,&nbsp;Hannah C. Cox,&nbsp;Stephanie B. Crowley,&nbsp;Susan Hiraki,&nbsp;Noriko N. Yokoyama,&nbsp;Noura S. Abul-Husn,&nbsp;James F. Amatruda,&nbsp;Michael J. Anderson,&nbsp;Xavier Bofill-De Ros,&nbsp;Ann G. Carr,&nbsp;Elizabeth C. Chao,&nbsp;Kenneth S. Chen,&nbsp;Shuo Gu,&nbsp;Cecilia Higgs,&nbsp;Jerry Machado,&nbsp;Deborah Ritter,&nbsp;Kris Ann P. Schultz,&nbsp;Emily R. Soper,&nbsp;Mona K. Wu,&nbsp;Jessica L. Mester,&nbsp;Jung Kim,&nbsp;William D. Foulkes,&nbsp;Leora Witkowski,&nbsp;Douglas R. Stewart","doi":"10.1155/2023/9537832","DOIUrl":"10.1155/2023/9537832","url":null,"abstract":"<div>\u0000 <p>Germline pathogenic variants in <i>DICER1</i> predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification are essential for reliable diagnosis of <i>DICER1-</i>related tumor predisposition and the identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for <i>DICER1</i> germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of <i>DICER1</i> experts joined ClinGen to form the <i>DICER1</i> and miRNA-Processing Genes Variant Curation Expert Panel (VCEP) to create <i>DICER1-</i>specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 <i>DICER1</i> variants were selected for piloting, including 14 known pathogenic/likely pathogenic (P/LP) variants, 12 known benign/likely benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the <i>DICER1-</i>specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating <i>DICER1</i> variants should consider adopting this classification framework to encourage consistency and improve objectivity.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10713350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44821886","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":"Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene","authors":"V. Manjunath,&nbsp;S. G. Thenral,&nbsp;B. R. Lakshmi,&nbsp;Atchayaram Nalini,&nbsp;A. Bassi,&nbsp;K. Priya Karthikeyan,&nbsp;K. Piyusha,&nbsp;R. Menon,&nbsp;A. Malhotra,&nbsp;L. S. Praveena,&nbsp;R. M. Anjanappa,&nbsp;S. M. Sakthivel Murugan,&nbsp;Kiran Polavarapu,&nbsp;Mainak Bardhan,&nbsp;V. Preethish-Kumar,&nbsp;Seena Vengalil,&nbsp;Saraswati Nashi,&nbsp;S. Sanga,&nbsp;M. Acharya,&nbsp;R. Raju,&nbsp;V. R. Pai,&nbsp;V. L. Ramprasad,&nbsp;R. Gupta","doi":"10.1155/2023/4362273","DOIUrl":"10.1155/2023/4362273","url":null,"abstract":"<div>\u0000 <p>The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the <i>α</i>, <i>β</i>, <i>γ</i>, and <i>δ</i> proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of <i>CAPN3</i>, <i>SGCB</i>, and <i>DYSF</i> variants was reported in more than 10% of our study cohort. The most common variant <i>SGCB</i> p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying <i>SGCB</i> p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set (<i>n</i> = 128) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the <i>SGCB</i> p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4362273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42681280","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":"Functional Assays Combined with Pre-mRNA-Splicing Analysis Improve Variant Classification and Diagnostics for Individuals with Neurofibromatosis Type 1 and Legius Syndrome","authors":"Hannie Douben,&nbsp;Marianne Hoogeveen-Westerveld,&nbsp;Mark Nellist,&nbsp;Jesse Louwen,&nbsp;Marian Kroos-de Haan,&nbsp;Mattijs Punt,&nbsp;Babeth van Ommeren,&nbsp;Leontine van Unen,&nbsp;Peter Elfferich,&nbsp;Esmee Kasteleijn,&nbsp;Yolande van Bever,&nbsp;Margreethe van Vliet,&nbsp;Rianne Oostenbrink,&nbsp;Jasper J. Saris,&nbsp;Anja Wagner,&nbsp;Yvette van Ierland,&nbsp;Tjakko van Ham,&nbsp;Rick van Minkelen","doi":"10.1155/2023/9628049","DOIUrl":"10.1155/2023/9628049","url":null,"abstract":"<div>\u0000 <p>Neurofibromatosis type 1 (NF1) and Legius syndrome (LS) are caused by inactivating variants in <i>NF1</i> and <i>SPRED1</i>. <i>NF1</i> encodes neurofibromin (NF), a GTPase-activating protein (GAP) for RAS that interacts with the <i>SPRED1</i> product, Sprouty-related protein with an EVH (Ena/Vasp homology) domain 1 (SPRED1). Obtaining a clinical and molecular diagnosis of NF1 or LS can be challenging due to the phenotypic diversity, the size and complexity of the <i>NF1</i> and <i>SPRED1</i> loci, and uncertainty over the effects of some <i>NF1</i> and <i>SPRED1</i> variants on pre-mRNA splicing and/or protein expression and function. To improve <i>NF1</i> and <i>SPRED1</i> variant classification and establish pathogenicity for <i>NF1</i> and <i>SPRED1</i> variants identified in individuals with NF1 or LS, we analyzed patient RNA by RT-PCR and performed <i>in vitro</i> exon trap experiments and estimated NF and SPRED1 protein expression, RAS GAP activity, and interaction. We obtained evidence to support pathogenicity according to American College of Medical Genetics guidelines for 73/114 variants tested, demonstrating the utility of functional approaches for <i>NF1</i> and <i>SPRED1</i> variant classification and NF and LS diagnostics.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/9628049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46169100","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":"A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay.","authors":"Hongzheng Dai, Wenmiao Zhu, Bo Yuan, Nicole Walley, Kelly Schoch, Yong-Hui Jiang, John A Phillips, Melissa S Jones, Pengfei Liu, David R Murdock, Lindsay C Burrage, Brendan Lee, Jill A Rosenfeld, Rui Xiao","doi":"10.1002/humu.24497","DOIUrl":"10.1002/humu.24497","url":null,"abstract":"<p><p>Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, while detection of single-exon CNVs remains challenging. A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individuals with homozygous single-exon deletions of TBCK (exon 23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzed single nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon 23 TBCK deletions. A fifth individual was diagnosed with the TBCK-related disorder due to a heterozygous exon 23 deletion in trans with a c.1860+1G>A (NM_001163435.2) pathogenic variant, and three additional heterozygous carriers were identified. Affected individuals and carriers were from diverse ethnicities including European Caucasian, South Asian, Middle Eastern, Hispanic American and African American, with only one family reporting consanguinity. RT-PCR revealed two out-of-frame transcripts related to the exon 23 deletion. Our results highlight the importance of identifying single-exon deletions in clinical ES, especially for genes carrying recurrent deletions. For patients with early-onset hypotonia and psychomotor delay, this single-exon TBCK deletion might be under-recognized due to technical limitations of ES.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1816-1823"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10556276","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}