Human Mutation最新文献

{"title":"A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and SRRM2 Haploinsufficiency","authors":"A. Pagnamenta, Jing Yu, T. Willis, Mona Hashim, E. Seaby, S. Walker, Jiaqi Xian, Emily W. Y. Cheng, A. L. T. Tavares, F. Forzano, H. Cox, T. Dabir, A. Brady, N. Ghali, S. Atanur, Sarah Ennis, D. Baralle, Jenny C. Taylor","doi":"10.1155/2023/6633248","DOIUrl":"https://doi.org/10.1155/2023/6633248","url":null,"abstract":"SRRM2 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 SRRM2. 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 SRRM2. 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\u0000 \u0000 \u0000 \u0000 \u0000 ∗\u0000 \u0000 \u0000 \u0000 and p.Ala2223Leufs\u0000 \u0000 \u0000 \u0000 \u0000 ∗\u0000 \u0000 \u0000 \u0000 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 CASR/PKD1 and SLC17A5, 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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, A. Allister, Gunnar Schmidt, Annette Otto, Kai Heinecke, Jördis Bax-Knoche, C. Beger, Sarah Becker, S. Bartels, T. Ripperger, J. Bohne, T. Dörk, B. Schlegelberger, W. Hofmann, D. Steinemann","doi":"10.1155/2023/6623515","DOIUrl":"https://doi.org/10.1155/2023/6623515","url":null,"abstract":"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 Mobster. A novel Alu element insertion in ATM 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 ATM transcripts. To manifest the direct association between the Alu element insertion and the aberrant splice pattern, HEK293T and MCF7 cells were transfected with wild-type or Alu element-carrying minigene constructs. On average, 77% of plasmid-derived transcripts lacked exon 54 in the presence of the Alu 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 ATM 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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, S. Thenral, B. R. Lakshmi, A. Nalini, A. Bassi, K. P. Karthikeyan, K. Piyusha, R. Menon, A. Malhotra, L. S. Praveena, R. Anjanappa, S. Murugan, K. Polavarapu, M. Bardhan, V. Preethish-Kumar, S. Vengalil, S. Nashi, S. Sanga, M. Acharya, R. Raju, V. Pai, V. Ramprasad, Rikita Gupta","doi":"10.1155/2023/4362273","DOIUrl":"https://doi.org/10.1155/2023/4362273","url":null,"abstract":"The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ 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 CAPN3, SGCB, and DYSF variants was reported in more than 10% of our study cohort. The most common variant SGCB 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 SGCB 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 (\u0000 \u0000 n\u0000 =\u0000 128\u0000 \u0000 ) 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 SGCB 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.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"H. Douben, M. Hoogeveen‐Westerveld, M. Nellist, Jesse Louwen, Marian Kroos-de Haan, Mattijs Punt, Babeth van Ommeren, L. V. van Unen, P. Elfferich, E. Kasteleijn, Y. van Bever, M. van Vliet, R. Oostenbrink, J. Saris, A. Wagner, Y. van Ierland, T. V. van Ham, R. van Minkelen","doi":"10.1155/2023/9628049","DOIUrl":"https://doi.org/10.1155/2023/9628049","url":null,"abstract":"Neurofibromatosis type 1 (NF1) and Legius syndrome (LS) are caused by inactivating variants in NF1 and SPRED1. NF1 encodes neurofibromin (NF), a GTPase-activating protein (GAP) for RAS that interacts with the SPRED1 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 NF1 and SPRED1 loci, and uncertainty over the effects of some NF1 and SPRED1 variants on pre-mRNA splicing and/or protein expression and function. To improve NF1 and SPRED1 variant classification and establish pathogenicity for NF1 and SPRED1 variants identified in individuals with NF1 or LS, we analyzed patient RNA by RT-PCR and performed in vitro 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 NF1 and SPRED1 variant classification and NF and LS diagnostics.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specifications of the ACMG/AMP Variant Classification Guidelines for Germline <i>DICER1</i> Variant Curation.","authors":"Jessica N Hatton, Megan N Frone, Hannah C Cox, Stephanie B Crowley, Susan Hiraki, Noriko N Yokoyama, Noura S Abul-Husn, James F Amatruda, Michael J Anderson, Xavier Bofill-De Ros, Ann G Carr, Elizabeth C Chao, Kenneth S Chen, Shuo Gu, Cecilia Higgs, Jerry Machado, Deborah Ritter, Kris Ann Schultz, Emily R Soper, Mona K Wu, Jessica L Mester, Jung Kim, William D Foulkes, Leora Witkowski, Douglas R Stewart","doi":"10.1155/2023/9537832","DOIUrl":"10.1155/2023/9537832","url":null,"abstract":"<p><p>Germline pathogenic variants in <i>DICER1</i> predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of <i>DICER1</i>-related tumor predisposition and 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>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","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":"Functional characterization of a novel TP53RK mutation identified in a family with Galloway-Mowat syndrome.","authors":"Ernestine Treimer,&nbsp;Tugba Kalayci,&nbsp;Sven Schumann,&nbsp;Ilknur Suer,&nbsp;Sara Greco,&nbsp;Denny Schanze,&nbsp;Michael J Schmeisser,&nbsp;Susanne J Kühl,&nbsp;Martin Zenker","doi":"10.1002/humu.24472","DOIUrl":"https://doi.org/10.1002/humu.24472","url":null,"abstract":"<p><p>Galloway-Mowat syndrome (GAMOS) is a very rare condition characterized by early-onset nephrotic syndrome and microcephaly with variable neurologic features. While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex, one of which is TP53RK. Here we describe a 3-year-old male with progressive microcephaly, neurodevelopmental deficits, and glomerular proteinuria. He was found to carry a novel homozygous TP53RK missense variant, c.163C>G (p.Arg55Gly), which was considered as potentially disease-causing. We generated a morpholino tp53rk knockdown model in Xenopus laevis showing that the depletion of endogenous Tp53rk caused abnormal eye and head development. This phenotype could be rescued by the expression of human wildtype TP53RK but not by the c.163C>G mutant nor by another previously described GAMOS-associated mutant c.125G>A (p.Gly42Asp). These findings support the pathogenic role of the novel TP53RK variant.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10825862","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 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":null,"pages":null},"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}

{"title":"AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders.","authors":"Johann Kaspar Lieberwirth,&nbsp;Benjamin Büttner,&nbsp;Chiara Klöckner,&nbsp;Konrad Platzer,&nbsp;Bernt Popp,&nbsp;Rami Abou Jamra","doi":"10.1002/humu.24451","DOIUrl":"https://doi.org/10.1002/humu.24451","url":null,"abstract":"<p><p>Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50% of the cases. Research analysis of unsolved cases can identify novel candidate genes but is time-consuming, subjective, and hard to compare between labs. The field, therefore, requires automated and standardized assessment methods to prioritize candidates for matchmaking. We developed AutoCaSc (https://autocasc.uni-leipzig.de) based on our candidate scoring scheme. We validated our approach using synthetic trios and real in-house trio ES data. AutoCaSc consistently (94.5% of all cases) scored the relevant variants in valid novel NDD genes in the top three ranks. In 93 real trio exomes, AutoCaSc identified most (97.5%) previously manually scored variants while evaluating additional high-scoring variants missed in manual evaluation. It identified candidate variants in previously undescribed NDD candidate genes (CNTN2, DLGAP1, SMURF1, NRXN3, and PRICKLE1). AutoCaSc enables anybody to quickly screen a variant for its plausibility in NDD. After contributing >40 descriptions of NDD-associated genes, we provide usage recommendations based on our extensive experience. Our implementation is capable of pipeline integration and therefore allows the screening of large cohorts for candidate genes. AutoCaSc empowers even small labs to a standardized matchmaking collaboration and to contribute to the ongoing identification of novel NDD entities.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10562862","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":"Cancer-causing MAP2K1 mutation in a mosaic patient with cardio-facio-cutaneous syndrome and immunodeficiency.","authors":"Victorya Zakharova,&nbsp;Elena Raykina,&nbsp;Irina Mersiyanova,&nbsp;Ekaterina Deordieva,&nbsp;Dmitry Pershin,&nbsp;Victorya Vedmedskia,&nbsp;Yulia Rodina,&nbsp;Natalia Kuzmenko,&nbsp;Michael Maschan,&nbsp;Anna Shcherbina","doi":"10.1002/humu.24463","DOIUrl":"https://doi.org/10.1002/humu.24463","url":null,"abstract":"<p><p>RASopathies are disorders caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. These syndromes share features of developmental delay, facial dysmorphisms, and defects in various organs, as well as cancer predisposition. Somatic mutations of the same pathway are one of the primary causes of cancer. It is thought that germline cancer-causing mutations would be embryonic lethal, as a more severe phenotype was shown in Drosophila and zebrafish embryos with cancer MAP2K1 mutations than in those with RASopathy mutations. Here we report the case of a patient with RASopathy caused by a cancer-associated MAP2K1 p.Phe53Leu mutation. The postzygotic mosaic nature of this mutation could explain the patient's survival.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10555473","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":"Characterization of a possible founder synonymous variant in TECTA in multiple individuals with autosomal recessive hearing loss.","authors":"Robert Chen,&nbsp;Maria Alejandra Diaz-Miranda,&nbsp;Erfan Aref-Eshghi,&nbsp;Tiffiney R Hartman,&nbsp;Christopher Griffith,&nbsp;Jennifer L Morrison,&nbsp;Patricia G Wheeler,&nbsp;Erin Torti,&nbsp;Gabriele Richard,&nbsp;Margaret Kenna,&nbsp;Elizabeth T Dechene,&nbsp;Nancy B Spinner,&nbsp;Renkui Bai,&nbsp;Laura K Conlin,&nbsp;Ian D Krantz,&nbsp;Sami S Amr,&nbsp;Minjie Luo","doi":"10.1002/humu.24443","DOIUrl":"https://doi.org/10.1002/humu.24443","url":null,"abstract":"<p><p>Synonymous variants have been shown to alter the correct splicing of pre-mRNAs and generate disease-causing transcripts. These variants are not an uncommon etiology of genetic disease; however, they are frequently overlooked during genetic testing in the absence of functional and clinical data. Here, we describe the occurrence of a synonymous variant [NM_005422.4 (TECTA):c.327C>T, p.(Gly109=)] in seven individuals with hearing loss from six unrelated families. The variant is not located near exonic/intronic boundaries but is predicted to impact splicing by activating a cryptic splicing donor site in exon 4 of TECTA. In vitro minigene assays show that the variant disrupts the reading frame of the canonical transcript, which is predicted to cause a premature termination codon 48 amino acids downstream of the variant, leading to nonsense-mediated decay. The variant is present in population databases, predominantly in Latinos of African ancestry, but is rare in other ethnic groups. Our findings suggest that this synonymous variant is likely pathogenic for TECTA-associated autosomal recessive hearing loss and seems to have arisen as a founder variant in this specific Latino subpopulation. This study demonstrates that synonymous variants need careful splicing assessment and support from additional testing methodologies to determine their clinical impact.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9106874","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}