Human Mutation最新文献

{"title":"Clinic Examination and Gene Diagnosis for a Birt–Hogg–Dubé Syndrome Family With a Novel flcn Frameshift Mutation Causing Nonsense-Mediated mRNA Degradation","authors":"Yang Xu,&nbsp;Jie Gao,&nbsp;Yang An,&nbsp;Chenxi Zou,&nbsp;Guoqing Ding,&nbsp;Guohua Yang","doi":"10.1155/humu/7194418","DOIUrl":"https://doi.org/10.1155/humu/7194418","url":null,"abstract":"<p><b>Background:</b> Birt–Hogg–Dubé syndrome (BHD) was an autosomal dominant disorder caused by a mutation in the folliculin (<i>FLCN</i>) gene and characterized by benign cutaneous fibrofolliculomas in the head and neck, pulmonary cysts, spontaneous pneumothorax, and combined renal tumors.</p><p><b>Methods:</b> This study reported a familial case presenting multiple pulmonary bullae, recurrent spontaneous pneumothorax, diffuse cystic lesions in both lungs, and renal cysts. To further clarify the diagnosis, next-generation sequencing (NGS) was performed in conjunction with the clinical diagnostic criteria for Birt–Hogg–Dubé. The eukaryotic recombinant expression vectors of pEGFP-C1-<i>FLCN</i> and knock-in <i>FLCN</i> mutation by CRISPR/Cas9 were conducted in 293 T and BEAS-2B cell lines. The mRNA and protein expression of the <i>FLCN</i> mutation were verified by fluorescence quantitative PCR and Western blot assay. Nonsense-mediated mRNA decay (NMD) assays and immunohistochemical assays were conducted to elucidate the pathogenicity of the mutation and explore potential mechanisms.</p><p><b>Results:</b> A unique, novel, unspecified significance <i>FLCN</i> mutation NM_144997.7: c.21_22del (p. Cys8 Profs ^∗28) in Exon 4 was detected in both patients. The results demonstrated that the newly identified <i>FLCN</i> frameshift mutation significantly decreased <i>FLCN</i> mRNA and protein expression. The NMD complex recognized and degraded mRNAs containing a premature termination codon (PTC) in the open reading frame of the <i>FLCN</i> frameshift mutation, resulting in haploinsufficiency and ultimately contributing to the manifestation of BHD. Protein expression on the AMP-activated protein kinase (AMPK), Wnt/<i>β</i>-catenin, and mammalian target of rapamycin (mTOR) signaling pathways by immunohistochemistry indicated that <i>FLCN</i> frameshift mutations were responsible for BHD through the activation of AMPK, Wnt/<i>β</i>-catenin, and mTOR signaling pathways.</p><p><b>Conclusion:</b> The study demonstrated that a novel <i>FLCN</i> frameshift mutation was responsible for the pathogenesis of BHD and preliminarily demonstrated that <i>FLCN</i> causes BHD through the AMPK, Wnt/<i>β</i>-catenin, and mTOR signaling pathways.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7194418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111160","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":"Incorporating Nanopore Sequencing Into a Diverse Diagnostic Toolkit for Incontinentia Pigmenti","authors":"Simone Ahting,&nbsp;Denny Popp,&nbsp;Henry Oppermann,&nbsp;Vincent Strehlow,&nbsp;Maria Fasshauer,&nbsp;Bernt Popp,&nbsp;Maike Karnstedt,&nbsp;Isabell Schumann","doi":"10.1155/humu/6657400","DOIUrl":"https://doi.org/10.1155/humu/6657400","url":null,"abstract":"<p>Incontinentia pigmenti (IP) is a rare hereditary disorder affecting 1.2 in 100,000 live births, predominantly females. Genetic analysis of IP is complicated by a homologous pseudogene, making conventional short-read sequencing challenging. While long-range PCR is typically used to overcome this, skewed X-inactivation detection can also aid in assigning variants to <i>IKBKG</i>. We employed a comprehensive approach, incorporating whole-exome sequencing (WES), long-range PCR, RT-PCR, X-inactivation analysis, and nanopore sequencing, to identify and accurately phase a small heterozygous deletion, NM_001099857.5: c.363_367del, p.(Leu122Glyfs ^∗14), in the <i>IKBKG</i> gene in an IP-affected family. The deletion was initially detected via WES, with skewed X-inactivation observed in both the proband and her mother. Long-range PCR specific to <i>IKBKG</i> confirmed the variant’s location in the <i>IKBKG</i> gene, not in the pseudogene. On the RNA level, the variant was undetectable, suggesting nonsense-mediated decay of the transcript. Nanopore sequencing precisely mapped the variant to <i>IKBKG</i> and analyzed the methylation status of both alleles, confirming the skewed X-inactivation, with the variant-carrying allele predominantly inactivated. This demonstrates the nanopore sequencing’s value in genetic diagnosis, enabling precise variant localization and analysis of X chromosome activation status in females with skewed X-inactivation, aiding in accurate diagnosis and understanding of IP.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6657400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121099","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":"Whole Genome Sequencing of “Mutation-Negative” Individuals With Cornelia de Lange Syndrome","authors":"Morad Ansari,&nbsp;Mihail Halachev,&nbsp;David Parry,&nbsp;Jose L. Campos,&nbsp;Elston N. D’Souza,&nbsp;Christopher Barnett,&nbsp;Andrew O. M. Wilkie,&nbsp;Angela Barnicoat,&nbsp;Chirag V. Patel,&nbsp;Elena Sukarova-Angelovska,&nbsp;Katta M. Girisha,&nbsp;Helen V. Firth,&nbsp;Katrina Prescott,&nbsp;Louise C. Wilson,&nbsp;Meriel McEntagart,&nbsp;Rosemarie Davidson,&nbsp;Sally Ann Lynch,&nbsp;Shelagh Joss,&nbsp;Simon T. Holden,&nbsp;Wayne K. Lam,&nbsp;Sanjay M. Sisodiya,&nbsp;Andrew J. Green,&nbsp;Gemma Poke,&nbsp;Nicola Whiffin,&nbsp;David R. FitzPatrick,&nbsp;Alison Meynert","doi":"10.1155/humu/4711663","DOIUrl":"https://doi.org/10.1155/humu/4711663","url":null,"abstract":"<p>This study was aimed at assessing the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing had not identified a causative variant. Short-read whole genome sequencing was performed on 195 individuals from 105 families, 108 of whom were affected. 100/108 of the affected individuals had prior relevant genetic testing, with no pathogenic variant being identified. The study group comprised 42 trios in which both parental samples were available for testing (42 affected individuals and 126 unaffected parents), 61 singletons (unrelated affected individuals), and two families with more than one affected individual. The results showed that 32 unrelated probands from 105 families (30.5%) had likely causative coding region-disrupting variants. Four loci were identified in &gt; 1 proband: <i>NIPBL</i> (10), <i>ANKRD11</i> (6), <i>EP300</i> (3), and <i>EHMT1</i> (2). Single variants were detected in the remaining genes (<i>EBF3</i>, <i>KMT2A</i>, <i>MED13L</i>, <i>NLGN3</i>, <i>NR2F1</i>, <i>PHIP</i>, <i>PUF60</i>, <i>SET</i>, <i>SETD5</i>, <i>SMC1A</i>, and <i>TBL1XR1</i>). Possibly causative variants in noncoding regions of <i>NIPBL</i> were identified in four individuals. Single de novo variants were identified in five genes not previously reported to be associated with any developmental disorder: <i>ARID3A</i>, <i>PIK3C3</i>, <i>MCM7</i>, <i>MIS18BP1</i>, and <i>WDR18</i>. The clustering of de novo noncoding variants implicates a single upstream open reading frame (uORF) and a small region in Intron 21 in <i>NIPBL</i> regulation. Causative variants in genes encoding chromatin-associated proteins, with no defined influence on cohesin function, appear to result in CdLS-like clinical features. This study demonstrates the clinical utility of whole genome sequencing as a diagnostic test in individuals presenting with CdLS or CdLS-like phenotypes.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4711663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121098","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 Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients","authors":"Igor Bychkov,&nbsp;Alexandra Filatova,&nbsp;Galina Baydakova,&nbsp;Nataliya Sikora,&nbsp;Emiliya Garifullina,&nbsp;Anna Bykova,&nbsp;Vyacheslav Tabakov,&nbsp;Alexandr Skretnev,&nbsp;Mikhail Skoblov,&nbsp;Ekaterina Zakharova","doi":"10.1155/humu/2250030","DOIUrl":"https://doi.org/10.1155/humu/2250030","url":null,"abstract":"<p>Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the <i>ARSB</i> gene. Herein, we present three patients with biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing of <i>ARSB</i> failed to identify one or both causative variants. RNA analysis of patients’ samples revealed alterations of the wild-type <i>ARSB</i> mRNA isoform in all cases, and one case required further analysis using whole genome sequencing. As a result, we identified one complex structural variant, which is a 52-kb insertion of the <i>LHFPL2</i> gene fragment in the <i>ARSB</i> Intron 4, derived from nonallelic homologous recombination and leading to premature transcription termination, a recurrent deep intronic variant leading to pseudoexon activation and an intragenic deletion altering the integrity and splicing of the <i>ARSB</i> Exon 2.</p><p>Using a minigene-based cellular model, we demonstrated that the identified pseudoexon can be efficiently blocked by antisense molecules incorporated into modified U7 small nuclear RNAs and circular RNAs. The same approach was used to block the overlapping polymorphic pseudoexon in the <i>ARSB</i> gene and increase the amount of wild-type mRNA isoform approximately twofold.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/2250030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113867","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":"An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene","authors":"Joshua S. Clayton,&nbsp;Mridul Johari,&nbsp;Rhonda L. Taylor,&nbsp;Lein Dofash,&nbsp;Georgina Allan,&nbsp;Gavin Monahan,&nbsp;Peter J. Houweling,&nbsp;Gianina Ravenscroft,&nbsp;Nigel G. Laing","doi":"10.1155/2024/6496088","DOIUrl":"https://doi.org/10.1155/2024/6496088","url":null,"abstract":"<p>The <i>ACTA1</i> gene encodes skeletal muscle alpha-actin, which forms the core of the sarcomeric thin filament in adult skeletal muscle. ACTA1 represents one of six highly conserved actin proteins that have all been associated with human disease. The first 15 pathogenic variants in <i>ACTA1</i> were reported in 1999, which expanded to 177 in 2009. Here, we update on the now 607 total variants reported in LOVD, HGMD, and ClinVar, which includes 343 reported pathogenic/likely pathogenic (P/LP) variants. We also provide suggested <i>ACTA1</i>-specific modifications to ACMG variant interpretation guidelines based on our analysis of known variants, gnomAD reports, and pathogenicity in other actin isoforms. Using these criteria, we report a total of 447 P/LP <i>ACTA1</i> variants. From a clinical perspective, the number of reported <i>ACTA1</i> disease phenotypes has grown from five to 20, albeit with some overlap. The vast majority (74%) of <i>ACTA1</i> variants cause nemaline myopathy (NEM), but there are increasing numbers that cause cardiomyopathy and novel phenotypes such as distal myopathy. We highlight challenges associated with identifying genotype–phenotype correlations for <i>ACTA1</i>. Finally, we summarize key animal models and review the current state of preclinical treatments for <i>ACTA1</i> disease. This update provides important resources and recommendations for the study and interpretation of <i>ACTA1</i> variants.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6496088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525499","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":"Biochemical and Genetic Testing of GAA in Over 30.000 Symptomatic Patients Suspected to Be Affected With Pompe Disease","authors":"Sukirthini Balendran-Braun,&nbsp;Ursula Vinatzer,&nbsp;Sandra Liebmann-Reindl,&nbsp;Manuela Lux,&nbsp;Petra Oliva,&nbsp;Stefaan Sansen,&nbsp;Thomas Mechtler,&nbsp;David C. Kasper,&nbsp;Berthold Streubel","doi":"10.1155/2024/6248437","DOIUrl":"https://doi.org/10.1155/2024/6248437","url":null,"abstract":"<p>Pompe disease (PD) is a rare autosomal recessive lysosomal disorder caused by loss-of-function of the <i>α</i>-glucosidase (<i>GAA</i>) gene. The deficient GAA enzyme activity may result in potential life-threatening muscle weakness, thus requiring a rapid diagnosis to initiate therapeutic interventions. In this large retrospective study, we analyzed 30.836 PD suspect samples from 57 countries using a two-step approach utilizing dried blood spots (DBSs): biochemical testing of GAA activity followed by complementary genetic sequencing of <i>GAA</i> in biochemically conspicuous cases. Of these 30.836 samples, 2% (<i>n</i> = 639) were excluded; accordingly, this study consisted of 30.193 cases. Biochemical testing of GAA enzyme activity showed normal values in 28.354 (93.90%) and enzyme activity below the cut-off in 1843 (6.10%) cases. These biochemically suspicious cases were genetically analyzed. We identified 723 Pompe cases with 283 different <i>GAA</i> alterations, and 98 variants have been unpublished so far. The most common variant was the splice variant c.-32-13T&gt;G (IVS1). Looking at the IVS1-genotype, the majority was compound heterozygous (<i>n</i> = 169) and identified in late-onset cases (<i>n</i> = 162). Comparison of early- versus late-onset cases to evaluate whether certain genotypes correlate with the age of onset revealed that homozygosity was predominantly found in infantile (85.65%) and compound heterozygosity in late-onset (76.9%) cases. Analysis of homozygous cases revealed 61% nonsense variants in the early stages and 87% missense variants in the late stages. Mapping of disease-associated (homozygous) missense variants to functional GAA protein domains showed that missense variants were found throughout GAA, but we identified enrichment in the catalytic domain. A strict genotype–phenotype correlation cannot be established; nevertheless, a phenotypic implication of some <i>GAA</i> variants could be drawn (e.g., c.896T&gt;C/p.L299P, c.2015G&gt;A/p.R672Q, and c.-32-13T&gt;G). The combined enzyme activity and genetic testing from DBS cards can reliably identify PD and significantly accelerate diagnosis. We identified new genetic variants that contribute to the spectrum of pathogenic variants of the <i>GAA</i> gene.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6248437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525102","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":"Impact of Gene Modifiers on Cystic Fibrosis Phenotypic Profiles: A Systematic Review","authors":"Anastasia Ward,&nbsp;Ramil Mauleon,&nbsp;Chee Y. Ooi,&nbsp;Nedeljka Rosic","doi":"10.1155/2024/6165547","DOIUrl":"https://doi.org/10.1155/2024/6165547","url":null,"abstract":"<p>Cystic fibrosis (CF) is a complex monogenic disorder with a large variability in disease severity. Growing evidence suggests that the variation observed depends not only on variations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>) gene but also on modifier genes. Utilizing five databases (including CINAHL, PubMed, Science Direct, Scopus, and Web of Science), a systematic review was conducted to examine the current literature on the known impacts of genomic variations in modifier genes on the CF disease progression, severity, and therapeutic response. A total of 70 full-text articles describing over 80 gene modifiers associated with CF were selected. The modifier genes included genes associated with the CFTR interactome, the inflammatory response, microbial profiles, and other genes affecting the critical physiological pathways of multiple organ systems, such as the respiratory and gastrointestinal systems. Limitations of the existing literature embrace the lack of clinical studies investigating pharmacogenetic impacts and the significance of gene modifiers on the CF clinical picture, including a limited number of replication and validation studies. Further investigations into other potential gene modifiers using genome-wide association studies are needed to critically explore new therapeutic targets and provide a better understanding of the CF disease phenotype under specific drug treatments.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6165547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443577","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":"Exonic Deletions and Deep Intronic Variants of the SLC26A4 Gene Contribute to the Genetic Diagnosis of Unsolved Patients With Enlarged Vestibular Aqueduct","authors":"Yongan Tian,&nbsp;Mengli Liu,&nbsp;Yu Lu,&nbsp;Xiaoyan Zhao,&nbsp;Zhiqiang Yan,&nbsp;Yi Sun,&nbsp;Jingyuan Ma,&nbsp;Wenxue Tang,&nbsp;Haili Wang,&nbsp;Hongen Xu","doi":"10.1155/2024/8444122","DOIUrl":"https://doi.org/10.1155/2024/8444122","url":null,"abstract":"<p>Enlarged vestibular aqueduct (EVA) is a frequently occurring inner ear malformation that associates with sensorineural hearing loss (SNHL), with <i>SLC26A4</i> being the responsible gene. Based on multiplex PCR enrichment and sequencing of the exonic and flanking regions of the <i>SLC26A4</i> gene, we developed a panel specifically for EVA and found that up to 95% of EVA patients in our Chinese cohorts carried biallelic <i>SLC26A4</i> pathogenic variants (M2). In this study, we tried to investigate the genetic etiology of 13 previously undiagnosed EVA patients with monoallelic (M1) or none (M0) <i>SLC26A4</i> variant using a stepwise approach, including copy number variation (CNV) analysis of multiplex PCR enrichment and next-generation sequencing data, single-molecule real-time (SMRT) sequencing of the whole <i>SLC26A4</i> gene, whole exome sequencing (WES), and whole genome sequencing (WGS). CNV analysis revealed deletions in Exons 1–3, Exons 5–6, and Exons 9–10 of the <i>SLC26A4</i> gene in seven patients, and SMRT sequencing identified the same heterozygous deep intronic variant (NM_000441.2:c.304+941C&gt;T) in two patients, resulting in a final diagnosis in 9/13 patients. Notably, the variants of Exons 9–10 deletion and c.304+941C&gt;T have not been reported previously. We further showed that the variant c.304+941C&gt;T led to the exonization of partial AluSz6 element (126 bp) where the variant is located through sequencing of the mRNA extracted from the blood of a heterozygous variant carrier. In conclusion, our stepwise approach improved the diagnosis rate of EVA, expanded the mutational spectrum of the <i>SLC26A4</i> gene, and highlighted the contribution of exonic deletions and deep intronic variants to EVA.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8444122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439069","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":"Clinical, Pathologic, and Genetic Spectrum of Collagen VI–Related Disorder in China—A Retrospective Observational Multicenter Study","authors":"Chaoping Hu,&nbsp;Yiyun Shi,&nbsp;Lei Zhao,&nbsp;Wenhua Zhu,&nbsp;Kexin Jiao,&nbsp;Lifei Yu,&nbsp;Xihua Li,&nbsp;Yi Wang","doi":"10.1155/2024/3503253","DOIUrl":"https://doi.org/10.1155/2024/3503253","url":null,"abstract":"<p><b>Background</b>: Collagen VI-related disorder (COLVI-RD) is one of the most common congenital muscular dystrophies. However, data is limited in China.</p><p><b>Methods</b>: We conducted a retrospective study at two tertiary centers. Clinical presentations, lab findings (including serum creatine kinase levels), muscle biopsy, and molecular test results for patients diagnosed with definite COLVI-RD were collected.</p><p><b>Results</b>: A total of 82 patients were enrolled in the study, including 4 with early–severe Ullrich congenital muscular dystrophy (E–S UCMD) (4.8%), 45 with moderate–progressive Ullrich congenital muscular dystrophy (M–P UCMD, 54.9%), 19 with mild UCMD (23.2%), and 14 with Bethlem myopathy (BM, 17.1%). Feeding difficulty, DDH, and neurogenic damage were more common in E–S and M–P UCMD, while contracture of distal joints, atrophic scars, and hyperkeratosis was more prominent in mild UCMD and BM. Seventy patients harbored 64 pathogenic mutations in COLVI-related genes: 28 patients in COL6A1 gene, 25 patients in the COL6A2 gene, and 17 patients in the COL6A3 gene, among which 33 mutations were novel. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, which were mostly located in N-terminus of THD, in a dominant pattern, while mutations in the COL6A2 gene were much more polymorphic, which spread throughout the whole length of the gene, in a dominant or recessive pattern. Immunofluorescence dual labeling of Collagen VI/IV in 44 patients showed complete deficiency of Collagen VI in 10 patients (22.7%), sarcolemma-specific Collagen VI deficiency in 25 patients (56.8%), and normal Collagen VI staining in 9 patients (20.5%).</p><p><b>Conclusion</b>: Our study reported the largest cohort of COLVI-RD in China, which showed M–P UCMD was the most common phenotype, followed by mild UCMD and BM. We identified 30 novel mutations and expanded the genetic spectrum. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, while mutations in the COL6A2 gene were much more polymorphic. For severe phenotypes, most mutations are sporadic, while some are AD or recessive inherited. For milder phenotypes, sporadic and AD inherited were both common, while only 1 patient with recessive mutations was observed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3503253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435434","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":"Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG","authors":"Sander Pajusalu,&nbsp;Mari-Anne Vals,&nbsp;Mercedes Serrano,&nbsp;Peter Witters,&nbsp;Anna Cechova,&nbsp;Tomáš Honzik,&nbsp;Andrew C. Edmondson,&nbsp;Can Ficicioglu,&nbsp;Rita Barone,&nbsp;Pascale De Lonlay,&nbsp;Claire-Marine Bérat,&nbsp;Sandrine Vuillaumier-Barrot,&nbsp;Christina Lam,&nbsp;Marc C. Patterson,&nbsp;Mirian C. H. Janssen,&nbsp;Esmeralda Martins,&nbsp;Dulce Quelhas,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Jehan Mousa,&nbsp;Roser Urreizti,&nbsp;Peter McWilliams,&nbsp;Frederique Vernhes,&nbsp;Horacio Plotkin,&nbsp;Eva Morava,&nbsp;Katrin Õunap","doi":"10.1155/2024/8813121","DOIUrl":"https://doi.org/10.1155/2024/8813121","url":null,"abstract":"<p>We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (<i>n</i> = 80) of participants, followed by p.Pro113Leu (21.2%, <i>n</i> = 29), and p.Phe119Leu (12.4%, <i>n</i> = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease.</p><p><b>Trial Registration:</b>NCT03173300.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8813121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429225","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}