Human Mutation最新文献

{"title":"Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal","authors":"H. D. West, M. Nellist, R. Brouwer, M. C. van den Hout-van Vroonhoven, Luiz Gustavo Dufner de Almeida, Femke Hendriks, P. Elfferich, Meera Raja, P. Giles, R. Alfano, A. Peron, Y. Sznajer, L. De Waele, A. Jansen, M. Koopmans, A. Kievit, Laura S. Farach, H. Northrup, J. Sampson, L. Thomas, W. V. van Ijcken","doi":"10.1155/2023/4899372","DOIUrl":"https://doi.org/10.1155/2023/4899372","url":null,"abstract":"Tuberous sclerosis complex (TSC) is caused by inactivating variants in TSC1 and TSC2. Somatic mosaicism, as well as the size and complexity of the TSC1 and TSC2 loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve TSC1 and TSC2 variant detection, we screened the TSC1 and TSC2 genomic regions using targeted HaloPlex custom capture and next-generation sequencing (NGS) in genomic DNA isolated from peripheral blood of individuals with definite, possible or suspected TSC in whom no disease-associated variant had been identified by previous diagnostic genetic testing. We obtained >95% target region coverage at a read depth of 20 and >50% coverage at a read depth of 300 and identified inactivating TSC1 or TSC2 variants in 83/155 individuals (54%); 65/113 (58%) with clinically definite TSC and 18/42 (43%) with possible or suspected TSC. These included 19 individuals with deep intronic variants and 54 likely cases of mosaicism (variant allele frequency 1-28%; median 7%). In 13 cases (8%), we identified a variant of uncertain significance (VUS). Targeted genomic NGS of TSC1 and TSC2 increases the yield of inactivating variants found in individuals with suspected TSC.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42260693","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":"Functional Characterization of Novel Lunatic Fringe Variants in Spondylocostal Dysostosis Type-III with Scoliosis","authors":"Parker Wengryn, K. C. Silveira, Connor Oborn, Carrie-Lynn Soltys, Alexander Beke, Inara Chacon-Fonseca, N. Damseh, Marco Quesada Rodriguez, R. Badilla-Porras, P. Kannu","doi":"10.1155/2023/5989733","DOIUrl":"https://doi.org/10.1155/2023/5989733","url":null,"abstract":"Scoliosis affects over four million Americans, with most cases having an idiopathic cause. Pathogenic variants in the LUNATIC FRINGE (LFNG) gene can cause spondylocostal dysostosis type-III (SCD3), which is a rare skeletal dysplasia characterized by the absence, fusion, or partial development of vertebrae and ribs. Acute restrictive lung disease and scoliosis may also be present in some cases. The variability in symptoms suggests that there may be other underlying pathological mechanisms that are yet to be discovered. We conducted an analysis of two novel LFNG variants, c.766G>A (p.G256S) and c.521G>A (p.R174H), that were observed in a patient with SCD3 phenotype and scoliosis. Characterizing these variants can help us better understand the relationship between genotype and phenotype. We assessed both variants for impaired glycosyltransferase activity, subcellular mislocalization, and aberrant pre-proprotein processing. Our results indicate that the p.G256S variant is enzymatically nonfunctional, while the p.R174H variant is functionally less effective. Both variants were correctly localized and processed. Our findings suggest that the hypomorphic variant (p.R174H) may have partially improved the patient’s stature, as evidenced by a lower arm span-to-height ratio, increased height, and more vertebrae. However, this variant did not appear to have any effect on the severity of vertebral malformations, including scoliosis. Further research is necessary to determine the extent to which variations in LFNG activity affect the presentation of SCD3.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42688441","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 Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models","authors":"Xin Zhu, Xiaoyin Tan, Junwen Wang, Limeng Dai, Jia Li, Xingying Guan, Ziyi Wang, Mao Zhang, Junyan Hu, Yun Bai, Hongen Guo","doi":"10.1155/2023/4834423","DOIUrl":"https://doi.org/10.1155/2023/4834423","url":null,"abstract":"Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43543879","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 Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)","authors":"K. Uguen, Chandran Ka, G. Collod-Béroud, M. Le Tertre, Julie Guellec, C. Férec, C. Béroud, I. Callebaut, G. Le Gac","doi":"10.1155/2023/5162256","DOIUrl":"https://doi.org/10.1155/2023/5162256","url":null,"abstract":"SLC40A1 is the sole iron export protein reported in mammals and is a key player in both cellular and systemic iron homeostasis. This unique iron exporter, which belongs to the major facilitator superfamily, is predominantly regulated by the hyposideremic hormone hepcidin. SLC40A1 dysfunction causes ferroportin disease, and autosomal dominant iron overload disorder characterized by cellular iron retention, principally in reticuloendothelial cells, correlating with high serum ferritin and low to normal transferrin saturation. Resistant to hepcidin, SLC40A1 mutations are rather associated with elevated plasma iron and parenchymal iron deposition, a condition that resembles HFE-related hemochromatosis and is associated with more clinical complications. With very few exceptions, only missense variations are reported at the SLC40A1 locus; this situation increasingly limits the establishment of pathogenicity. In this mutation update, we provide a comprehensive review of all the pathogenic or likely pathogenic variants, variants of unknown significance, and benign or likely benign SLC40A1 variants. The classification is essentially determined using functional, structural, segregation, and recurrence data. We furnish new information on genotype-phenotype correlations for loss-of-function, gain-of-function, and other SLC40A1 variants, confirming the existence of wide clinical heterogeneity and the potential for misdiagnosis. All information is recorded in a locus-specific online database.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41360231","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":"Balanced Translocation Disrupting JAG1 Identified by Optical Genomic Mapping in Suspected Alagille Syndrome","authors":"Yi-Qiong Zhang, Pengzhao Gao, J. Yang, Jing Zhang, Yudong Lu, Jian-She Wang","doi":"10.1155/2023/5396281","DOIUrl":"https://doi.org/10.1155/2023/5396281","url":null,"abstract":"We report the clinical and genetic features of a Han Chinese boy who presented with disease suspect for Alagille syndrome (ALGS). Multiple genetic analyses (panel sequencing, multiplex-ligation-dependent probe amplification, and whole genome sequencing) failed to uncover a causative variant. Optical genomic mapping detected a reciprocal translocation between chromosomes 4 and 20, interrupting JAG1. Long-range polymerase chain reaction and targeted sequencing identified the exact breakpoints. Sanger sequencing and reanalysis of genome sequencing raw data further confirmed the result. This translocation is expected to generate aberrant JAG1 transcripts that lead to complete loss of JAG1 expression. This is the first t(4;20)(q22.1;p12.2) balanced translocation detected by optical genomic mapping and characterized at base-pair resolution in ALGS. Our approach permitted precise diagnosis and genetic counseling.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42609430","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":"Frequency and Functional Characterization of RUNX1 Germline Variants in Myeloid Neoplasms","authors":"N. J. Nitschke, M. Almosailleakh, Y. Niu, J. W. Hansen, K. Raaschou-Jensen, J. S. Jespersen, M. Severinsen, A. Roug, M. Frödin, J. Weischenfeldt, M. Andersen, K. Grønbæk","doi":"10.1155/2023/4738660","DOIUrl":"https://doi.org/10.1155/2023/4738660","url":null,"abstract":"Current estimates suggest that up to 10% of patients with myeloid neoplasms (MN) harbor variants associated with a germline predisposition. A pathogenic variant in the runt-related transcription factor 1 gene (RUNX1) is a frequent cause of germline predisposition to MN. RUNX1 variants detected in tumor tissue at a VAF close to 50% are potentially germline and causative of RUNX1 familial platelet disorder with associated myeloid malignancies. Previous studies have found germline RUNX1 variants in 3% of patients with acute myeloid leukemia; however, the frequency of germline RUNX1 variants in less advanced myeloid neoplasms has not been examined. We screened 590 patients suspected of MN, excluding myeloproliferative neoplasms, for germline variants in RUNX1. We found RUNX1 variants in 83 patients (14%) by targeted sequencing of tumor tissue. In 40 patients (6.8%), the VAF of RUNX1 was above 30%. In 32 of the 40 patients, skin biopsies were available and used for Sanger sequencing to assess the germline status. Two of the tested variants (6.3%) were confirmed as germline, and both variants were curated as variants of unknown significance. To further explore the pathogenicity of these variants, we implemented a novel CRISPR-Select functional genetic assay. The assay demonstrated a profound effect on proliferation in K562 cells for a known pathogenic variant but no effect for the two germline variants detected in the study. We therefore propose that both germline variants are classified as likely benign. In this study, we show that RUNX1 germline variants are rare in Danish patients with MN and use a novel assay for functional classification of germline RUNX1 variants.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47740432","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":"Reasons and Resolutions for Inconsistent Variant Interpretation","authors":"Liling Lin, H. Pan, Y. Qi, Yinan Ma, L. Qiu","doi":"10.1155/2023/4955235","DOIUrl":"https://doi.org/10.1155/2023/4955235","url":null,"abstract":"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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"G. Lazarian, B. Leroy, F. Theves, M. Hormi, R. Letestu, V. Eclache, G. Tueur, A. Ameur, A. Bidet, P. Cornillet‐Lefèbvre, F. Davi, E. Delabesse, M. Estienne, P. Etancelin, O. Kosmider, S. Laibe, M. Muller, N. Nadal, Dina Naguib, C. Pastoret, S. Poulain, P. Sujobert, L. Véronèse, Samia Imache, V. Lefebvre, F. Cymbalista, F. Baran-Marszak, T. Soussi","doi":"10.1155/2023/4880113","DOIUrl":"https://doi.org/10.1155/2023/4880113","url":null,"abstract":"TP53 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 TP53 abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of TP53 variants in CLL, 1,056 TP53 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 TP53 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 TP53 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 TP53 status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple TP53 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 TP53 mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Marcello Scala, P. de Marco, V. Guerriero, M. Ognibene, F. Madia, Sara Guerrisi, M. Di Duca, M. Torre, Serena Tamburro, P. Scudieri, G. Piccolo, G. Mattioli, F. Buffelli, P. Uva, D. Vozzi, E. Fulcheri, P. Striano, M. Diana, F. Zara","doi":"10.1155/2023/3160653","DOIUrl":"https://doi.org/10.1155/2023/3160653","url":null,"abstract":"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 NF1 variant NM_001042492.3: c.4271delC p.(Ala1424Glufs\u0000 \u0000 \u0000 \u0000 \u0000 ∗\u0000 \u0000 \u0000 \u0000 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\u0000 \u0000 \u0000 \u0000 \u0000 ∗\u0000 \u0000 \u0000 \u0000 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 NF1. 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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Phenotype Morbidity Description of SATB2-Associated Syndrome","authors":"Y. Zarate, K. Bosanko, Amrit Kannan, Ashlen Thomason, Beth Nutt, Nihit Kumar, K. Simmons, Aaron Hiegert, Larry D Hartzell, Adam Johnson, Tabitha Prater, Eduardo Pérez-Palma, Tobias Brünger, A. Stefanski, D. Lal, A. Caffrey","doi":"10.1155/2023/8200176","DOIUrl":"https://doi.org/10.1155/2023/8200176","url":null,"abstract":"Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2. 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 (\u0000 \u0000 n\u0000 =\u0000 10\u0000 \u0000 ), 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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}