Human Mutation最新文献

{"title":"A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2","authors":"Maria Zanti,&nbsp;Denise G. O′Mahony,&nbsp;Michael T. Parsons,&nbsp;Hongyan Li,&nbsp;Joe Dennis,&nbsp;Kristiina Aittomäkkiki,&nbsp;Irene L. Andrulis,&nbsp;Hoda Anton-Culver,&nbsp;Kristan J. Aronson,&nbsp;Annelie Augustinsson,&nbsp;Heiko Becher,&nbsp;Stig E. Bojesen,&nbsp;Manjeet K. Bolla,&nbsp;Hermann Brenner,&nbsp;Melissa A. Brown,&nbsp;Saundra S. Buys,&nbsp;Federico Canzian,&nbsp;Sandrine M. Caputo,&nbsp;Jose E. Castelao,&nbsp;Jenny Chang-Claude,&nbsp; GC-HBOC study Collaborators,&nbsp;Kamila Czene,&nbsp;Mary B. Daly,&nbsp;Arcangela De Nicolo,&nbsp;Peter Devilee,&nbsp;Thilo Dörk,&nbsp;Alison M. Dunning,&nbsp;Miriam Dwek,&nbsp;Diana M. Eccles,&nbsp;Christoph Engel,&nbsp;D. Gareth Evans,&nbsp;Peter A. Fasching,&nbsp;Manuela Gago-Dominguez,&nbsp;Montserrat García-Closas,&nbsp;José A. García-Sáenz,&nbsp;Aleksandra Gentry-Maharaj,&nbsp;Willemina R. R. Geurts - Giele,&nbsp;Graham G. Giles,&nbsp;Gord Glendon,&nbsp;Mark S. Goldberg,&nbsp;Encarna B. Gómez Garcia,&nbsp;Melanie Güendert,&nbsp;Pascal Guénel,&nbsp;Eric Hahnen,&nbsp;Christopher A. Haiman,&nbsp;Per Hall,&nbsp;Ute Hamann,&nbsp;Elaine F. Harkness,&nbsp;Frans B. L. Hogervorst,&nbsp;Antoinette Hollestelle,&nbsp;Reiner Hoppe,&nbsp;John L. Hopper,&nbsp;Claude Houdayer,&nbsp;Richard S. Houlston,&nbsp;Anthony Howell,&nbsp; ABCTB Investigators,&nbsp;Milena Jakimovska,&nbsp;Anna Jakubowska,&nbsp;Helena Jernström,&nbsp;Esther M. John,&nbsp;Rudolf Kaaks,&nbsp;Cari M. Kitahara,&nbsp;Stella Koutros,&nbsp;Peter Kraft,&nbsp;Vessela N. Kristensen,&nbsp;James V. Lacey,&nbsp;Diether Lambrechts,&nbsp;Melanie Léoné,&nbsp;Annika Lindblom,&nbsp;Jan Lubiński,&nbsp;Michael Lush,&nbsp;Arto Mannermaa,&nbsp;Mehdi Manoochehri,&nbsp;Siranoush Manoukian,&nbsp;Sara Margolin,&nbsp;Maria Elena Martinez,&nbsp;Usha Menon,&nbsp;Roger L. Milne,&nbsp;Alvaro N. Monteiro,&nbsp;Rachel A. Murphy,&nbsp;Susan L. Neuhausen,&nbsp;Heli Nevanlinna,&nbsp;William G. Newman,&nbsp;Kenneth Offit,&nbsp;Sue K. Park,&nbsp;Paul James,&nbsp;Paolo Peterlongo,&nbsp;Julian Peto,&nbsp;Dijana Plaseska-Karanfilska,&nbsp;Kevin Punie,&nbsp;Paolo Radice,&nbsp;Muhammad U. Rashid,&nbsp;Gad Rennert,&nbsp;Atocha Romero,&nbsp;Efraim H. Rosenberg,&nbsp;Emmanouil Saloustros,&nbsp;Dale P. Sandler,&nbsp;Marjanka K. Schmidt,&nbsp;Rita K. Schmutzler,&nbsp;Xiao-Ou Shu,&nbsp;Jacques Simard,&nbsp;Melissa C. Southey,&nbsp;Jennifer Stone,&nbsp;Dominique Stoppa-Lyonnet,&nbsp;Rulla M. Tamimi,&nbsp;William J. Tapper,&nbsp;Jack A. Taylor,&nbsp;Soo Hwang Teo,&nbsp;Lauren R. Teras,&nbsp;Mary Beth Terry,&nbsp;Mads Thomassen,&nbsp;Melissa A. Troester,&nbsp;Celine M. Vachon,&nbsp;Ana Vega,&nbsp;Maaike P. G. Vreeswijk,&nbsp;Qin Wang,&nbsp;Barbara Wappenschmidt,&nbsp;Clarice R. Weinberg,&nbsp;Alicja Wolk,&nbsp;Wei Zheng,&nbsp;Bingjian Feng,&nbsp;Fergus J. Couch,&nbsp;Amanda B. Spurdle,&nbsp;Douglas F. Easton,&nbsp;David E. Goldgar,&nbsp;Kyriaki Michailidou","doi":"10.1155/2023/9961341","DOIUrl":"10.1155/2023/9961341","url":null,"abstract":"<div>\u0000 <p>A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of <i>BRCA1</i> and <i>BRCA2</i> variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in <i>BRCA1</i>, <i>BRCA2</i>, and other high-risk genes with known penetrance.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/9961341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135553037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype and Phenotype Characteristics of Chinese Pediatric Patients with Primary Hyperoxaluria","authors":"Yucheng Ge,&nbsp;Yukun Liu,&nbsp;Ruichao Zhan,&nbsp;Zhenqiang Zhao,&nbsp;Jun Li,&nbsp;Wenying Wang,&nbsp;Ye Tian","doi":"10.1155/2023/4875680","DOIUrl":"10.1155/2023/4875680","url":null,"abstract":"<div>\u0000 <p>Primary hyperoxaluria (PH) is a rare monogenic disorder characterized by recurrent kidney stones, nephrocalcinosis, and renal impairment. To study the genotype and phenotype characteristics, we evaluated the clinical data of 42 Chinese pediatric PH patients who were diagnosed from May 2016 to April 2022. We found that patients with the PH3 type showed an earlier age of onset than those with the PH1 and PH2 types (1 versus 5 and 8 years, respectively, <i>P</i> &lt; 0.001). Urine citrate was significantly lower in PH1 and PH2 patients than that in PH3 patients (91.81 and 85.56 versus 163.9 <i>μ</i>g/mg, respectively, <i>P</i> = 0.044). Spot urine oxalate levels were slightly higher in PH1 than that in PH2 and PH3 patients (457.9 versus 182.38 and 309.14 <i>μ</i>g/mg, respectively, <i>P</i> = 0.189). A significant negative correlation between the urine calcium/creatinine ratio and the oxalate/creatinine ratio was observed in the entire PH cohort (<i>r</i> = −0.360, <i>P</i> = 0.04) and the PH3 cohort (<i>r</i> = −0.674, <i>P</i> = 0.003). PH-causative genes showed hotspot mutations or regions, including c.815_816insGA and c.33dup in <i>AGXT</i>, 864_865del in <i>GRHPR</i>, and exon 6 skipping and c.769T&gt;G in <i>HOGA1</i>. In the PH1 cohort, the estimated glomerular filtration rate (eGFR) was lowest in patients with heterozygous c.33dup. In the PH3 cohort, patients with heterozygous exon 6 skipping presented the lowest eGFR and a significant decrease in the renal survival advantage. In summary, PH1 patients exhibit much more severe phenotypes than those with other types. Hotspot mutations or regions exist in patients with all types of PH and show differences among ethnicities. Genotype-phenotype correlations are observed in PH1 and PH3.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/4875680","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134912511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of Synonymous and Missense Mutations in JAK3 Gene Contributes to Severe Combined Immunodeficiency in One Child","authors":"Xingcui Wang,&nbsp;Rujin Tian,&nbsp;Haozheng Zhang,&nbsp;Mohnad Abdalla,&nbsp;Lu Bai,&nbsp;Yuqiang Lv,&nbsp;Min Gao,&nbsp;Guiyu Lin,&nbsp;Qinghua Liu,&nbsp;Yi Liu,&nbsp;Qiuxia He,&nbsp;Dong Wang,&nbsp;Kaihui Zhang","doi":"10.1155/2023/6633251","DOIUrl":"10.1155/2023/6633251","url":null,"abstract":"<div>\u0000 <p>Janus kinase 3 (JAK3, NP_000206.2) is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction JAK/STAT pathway. <i>JAK3</i> gene variants can lead to autosomal recessive severe combined immunodeficiency (SCID), which is T-cell-negative, B-cell-positive, and NK-cell-negative (OMIM: 600802). We have detected one infant suffering from cytomegalovirus, fever, and impaired respiratory function with low lymphocytes and immunoglobulin. Two compound heterozygous variants, c.1914G&gt;T (p.L638=) and c.1048C&gt;T (p.R350W), were identified in the proband, each of which was inherited from one unaffected parent. Analysis of splicing was carried out by the Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay which both showed a deletion of exon 14 (128 bp) resulting from the c.1914G&gt;T variant at the mRNA level. Bioinformatic analysis for the reported c.1048C&gt;T (p.R350W) variant suggests that the variant is pathogenic. Based on the clinical characteristics of the patient and the functional verification of the gene variants, our pediatricians finally have diagnosed the infant as SCID (OMIM: 600802). The study is the first study regarding a synonymous variant of <i>JAK3</i> gene influencing alternative splicing. Our findings expand the mutation spectrum leading to JAK3 deficiency-related diseases and provide exact information for genetic counseling.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6633251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135690439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The UCMD-Causing COL6A1 (c.930 + 189C > T) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains","authors":"Carolin D. Freiburg,&nbsp;Herimela Solomon-Degefa,&nbsp;Patrick Freiburg,&nbsp;Matthias Mörgelin,&nbsp;Véronique Bolduc,&nbsp;Sebastian Schmitz,&nbsp;Pierpaolo Ala,&nbsp;Francesco Muntoni,&nbsp;Elmar Behrmann,&nbsp;Carsten G. Bönnemann,&nbsp;Alvise Schiavinato,&nbsp;Mats Paulsson,&nbsp;Raimund Wagener","doi":"10.1155/2023/6892763","DOIUrl":"10.1155/2023/6892763","url":null,"abstract":"<div>\u0000 <p>Collagen VI is a unique member of the collagen family. Its assembly is a complex multistep process and the vulnerability of the process is manifested in muscular diseases. Mutations in <i>COL6A1</i>, <i>COL6A2</i>, and <i>COL6A3</i> lead to the severe Ullrich Congenital Muscular Dystrophy (UCMD) and a spectrum of disease of varying severity including the milder Bethlem muscular dystrophy. The recently identified dominant intronic mutation in <i>COL6A1</i> (<i>c</i>.930 + 189<i>C</i> &gt; <i>T</i>) leads to the partial in-frame insertion of a pseudoexon between exon 11 and exon 12. The pseudoexon is translated into 24 amino acid residues in the N-terminal region of the triple helix and results in the interruption of the typical G-X-Y motif. This recurrent <i>de novo</i> mutation leads to UCMD with a severe progression within the first decade of life. Here, we demonstrate that a mutation-specific antibody detects the mutant chain colocalizing with wild type collagen VI in the endomysium in patient muscle. Surprisingly, in the cell culture of patient dermal fibroblasts, the mutant chain is secreted as a single <i>α</i> chain, while in parallel, normal collagen VI tetramers are assembled with the wild-type <i>α</i>1 chain. The mutant chain cannot be incorporated into collagen VI tetramers but forms large aggregates in the extracellular matrix that may retain the ability to interact with collagen VI and potentially with other molecules. Also, <i>α</i>1 chain-deficient WI-26 VA4 cells transfected with the mutant <i>α</i>1 chain do not assemble collagen VI tetramers but, instead, form aggregates. Interestingly, both the wild type and the mutant single <i>α</i>1 chains form amorphous aggregates when expressed in HEK293 cells in the absence of <i>α</i>2 and <i>α</i>3 chains. The detection of aggregated, assembly incompetent, mutant collagen VI <i>α</i>1 chains provides novel insights into the disease pathophysiology of UCMD patients with the <i>COL6A1</i> (<i>c</i>.930 + 189<i>C</i> &gt; <i>T</i>) mutation.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6892763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43551312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation in Monogenic Diabetes of the Impact of GCK, HNF1A, and HNF4A Variants on Splicing through the Combined Use of In Silico Tools and Minigene Assays","authors":"Delphine Bouvet,&nbsp;Amélie Blondel,&nbsp;Jean-Madeleine de Sainte Agathe,&nbsp;Gwendoline Leroy,&nbsp;Cécile Saint-Martin,&nbsp;Christine Bellanné-Chantelot","doi":"10.1155/2023/6661013","DOIUrl":"10.1155/2023/6661013","url":null,"abstract":"<div>\u0000 <p>Variants in <i>GCK</i>, <i>HNF1A</i>, and <i>HNF4A</i> genes are the three main causes of monogenic diabetes. Determining the molecular etiology is essential for patients with monogenic diabetes to benefit from the most appropriate treatment. The increasing number of variants of unknown significance (VUS) is a major issue in genetic diagnosis, and assessing the impact of variants on RNA splicing is challenging, particularly for genes expressed in tissues not easily accessible as in monogenic diabetes. The in vitro functional splicing assay based on a minigene construct is an appropriate approach. Here, we performed in silico analysis using SpliceAI and SPiP and prioritized 36 spliceogenic variants in <i>GCK</i>, <i>HNF1A</i>, and <i>HNF4A</i>. Predictions were secondarily compared with Pangolin and AbSplice-DNA bioinformatics tools which include tissue-specific annotations. We assessed the effect of selected variants on RNA splicing using minigene assays. These assays validated splicing defects for 33 out of 36 spliceogenic variants consisting of exon skipping (15%), exonic deletions (18%), intronic retentions (24%), and complex splicing patterns (42%). This provided additional evidence to reclassify 23 out of 31 (74%) VUS including missense, synonymous, and intronic noncanonical splice site variants as likely pathogenic variants. Comparison of in silico analysis with minigene results showed the robustness of bioinformatics tools to prioritize spliceogenic variants, but revealed inconsistencies in the location of cryptic splice sites underlying the importance of confirming predicted splicing alterations with functional splicing assays. Our study underlines the feasibility and the benefits of implementing minigene-splicing assays in the genetic testing of monogenic diabetes after a prior in-depth in silico analysis.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6661013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49033606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-Onset Aortic Dissection: Characterization of a New Pathogenic Splicing Variation in the MYH11 Gene with Several In-Frame Abnormal Transcripts","authors":"Pauline Arnaud,&nbsp;Margaux Cadenet,&nbsp;Zakaria Mougin,&nbsp;Carine Le Goff,&nbsp;Sébastien Perbet,&nbsp;Mathilde Francois,&nbsp;Sophie Dupuis-Girod,&nbsp;Catherine Boileau,&nbsp;Nadine Hanna","doi":"10.1155/2023/1410230","DOIUrl":"10.1155/2023/1410230","url":null,"abstract":"<div>\u0000 <p>Rare pathogenic variants in the <i>MYH11</i> gene are responsible for thoracic aortic aneurysms and dissections. They are usually heterozygous missense variants or in-frame deletions of several amino acids without alteration of the reading frame and mainly affect the coiled-coil domain of the protein. Variants leading to a premature stop codon have been described in patients with another phenotype, megacystis-microcolon-intestinal hypoperistalsis syndrome, with an autosomal recessive inheritance. The physiopathological mechanisms arising from the different genetic alterations affecting the <i>MYH11</i> gene are still poorly understood. Consequently, variants of unknown significance are relatively frequent in this gene. We have identified a variant affecting the consensus donor splice site of exon 29 in the <i>MYH11</i> gene in a patient who suddenly died from an aortic type A dissection at the age of 23 years old. A transcript analysis on cultured fibroblasts has highlighted several abnormal transcripts including two in-frame transcripts. The first one is a deletion of the last 78 nucleotides of exon 29, corresponding to the use of a cryptic alternative donor splice site; the second one corresponds to an exon 29 skipping. Familial screening has revealed that this molecular event occurred <i>de novo</i> in the proband. Taken together, these experiments allowed us to classify this variant as pathogenic. This case underlines the challenging aspect of the discovery of variations in the <i>MYH11</i> gene for which the consequences on splicing should be systematically studied in detail.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/1410230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49534373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy","authors":"Aurélie Gouronc,&nbsp;Elodie Javey,&nbsp;Anne-Sophie Leuvrey,&nbsp;Elsa Nourisson,&nbsp;Sylvie Friedmann,&nbsp;Valérie Reichert,&nbsp;Nicolas Derive,&nbsp;Christine Francannet,&nbsp;Boris Keren,&nbsp;Jonathan Lévy,&nbsp;Marc Planes,&nbsp;Lyse Ruaud,&nbsp;Jeanne Amiel,&nbsp;Hélène Dollfus,&nbsp;Sophie Scheidecker,&nbsp;Jean Muller","doi":"10.1155/2023/2564200","DOIUrl":"10.1155/2023/2564200","url":null,"abstract":"<div>\u0000 <p>Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a <i>de novo</i> pathogenic variant in <i>trans</i> of an inherited pathogenic variant. These two genetic mechanisms are expected to be extremely rare, and few data are available in the literature, especially regarding ciliopathies. In this study, we investigated 940 individuals (812 families) with a suspected ciliopathy by Sanger sequencing, high-throughput sequencing and/or SNP array analysis and performed a literature review of UPD and <i>de novo</i> variants in ciliopathies. In a large cohort of 623 individuals (511 families) with a molecular diagnosis of ciliopathy (mainly Bardet-Biedl syndrome and Alström syndrome), we identified five UPD, revealing an inherited pathogenic variant and five pathogenic variants of <i>de novo</i> appearance (in <i>trans</i> of another pathogenic variant). Moreover, from these ten cases, we reported 15 different pathogenic variants of which five are novel. We demonstrated a relatively high prevalence of UPD and <i>de novo</i> variants in a large cohort of ciliopathies and highlighted the importance of identifying such rare genetic events, especially for genetic counseling.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/2564200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64792931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Constitutively Active c.98G > C, p.(R33P) Variant in RAB11A Associated with Intellectual Disability Promotes Neuritogenesis and Affects Oligodendroglial Arborization","authors":"Yumi Tsuneura,&nbsp;Taeko Kawai,&nbsp;Keitaro Yamada,&nbsp;Shintaro Aoki,&nbsp;Mitsuko Nakashima,&nbsp;Shima Eda,&nbsp;Tohru Matsuki,&nbsp;Masashi Nishikawa,&nbsp;Koh-ichi Nagata,&nbsp;Yasushi Enokido,&nbsp;Hirotomo Saitsu,&nbsp;Atsuo Nakayama","doi":"10.1155/2023/8126544","DOIUrl":"10.1155/2023/8126544","url":null,"abstract":"<div>\u0000 <p>Whole exome sequencing/whole genome sequencing has accelerated the identification of novel genes associated with intellectual disabilities (ID), and <i>RAB11A</i> which encodes an endosomal small GTPase is among them. However, consequent neural abnormalities have not been studied, and pathophysiological mechanisms underlying the ID and other clinical features in patients harboring <i>RAB11A</i> variants remain to be clarified. In this study, we report a novel <i>de novo</i> missense variant in <i>RAB11A</i>, NM_004663.5: <i>c</i>.98<i>G</i> &gt; <i>C</i>, which would result in NP_004654.1: p.(R33P) substitution, in a Japanese boy with severe ID and hypomyelination. Biochemical analyses indicated that the RAB11A-R33P is a gain-of-function, constitutively active variant. Accordingly, the introduction of the RAB11A-R33P promoted neurite extension in neurons like a known constitutively active variant Rab11A-Q70L. In addition, the RAB11A-R33P induced excessive branching with thinner processes in oligodendrocytes. These results indicate that the gain-of-function RAB11A-R33P variant in association with ID and hypomyelination affects neural cells and can be deleterious to them, especially to oligodendrocytes, and strongly suggest the pathogenic role of the RAB11A-R33P variant in neurodevelopmental impairments, especially in the hypomyelination.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/8126544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42621457","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":"Phenotypic Diversity in GNAO1 Patients: A Comprehensive Overview of Variants and Phenotypes","authors":"Maria Sáez González,&nbsp;Kes Kloosterhuis,&nbsp;Laura van de Pol,&nbsp;Frank Baas,&nbsp;Harald Mikkers","doi":"10.1155/2023/6628283","DOIUrl":"10.1155/2023/6628283","url":null,"abstract":"<div>\u0000 <p>GNAO1 disorder is a rare autosomal dominant neurodevelopmental syndrome that is clinically manifested by developmental delay, (early onset) epilepsy, and movement disorders. Clinical symptoms appear very heterogeneous in nature and severity, as well as the response of GNAO1 patients to available medication varies. Pathogenic <i>GNAO1</i> variants have been found mainly scattered throughout the gene although certain mutation hotspots affecting the function of the encoded G<i>α</i>o proteins exist. <i>GNAO1</i> variants only partially explain the diverse phenotypic spectrum observed but full stratification has been hampered by the limited number of patients. The aim of this review was to generate a comprehensive overview of the germline variants in <i>GNAO1</i> and provide insight into the phenotypic diversity of the GNAO1 disorder. We compiled a list of 398 <i>GNAO1</i> germline variants. In addition, we provide the <i>GNAO1</i> variants and associated phenotypes of 282 GNAO1 patients reported in case reports, whole genome sequencing studies, genetic variant databases, and 8 novel GNAO1 patients that were not described before. This has resulted in a list of 107 (likely) pathogenic <i>GNAO1</i> variants. Available phenotypic data was utilized to quantitatively assess the genetic and phenotypic diversity of the GNAO1 disorder and discuss the outcomes. This inventory forms the basis for a <i>GNAO1</i> variant database that will be updated continuously. Moreover, it will aid genetic diagnostics, medical decision-making, prognostication, and research on the mechanisms underlying the GNAO1 disorder.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/6628283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45909106","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":"BTKbase, Bruton Tyrosine Kinase Variant Database in X-Linked Agammaglobulinemia: Looking Back and Ahead","authors":"Gerard C. P. Schaafsma,&nbsp;Jouni Väliaho,&nbsp;Qing Wang,&nbsp;Anna Berglöf,&nbsp;Rula Zain,&nbsp;C. I. Edvard Smith,&nbsp;Mauno Vihinen","doi":"10.1155/2023/5797541","DOIUrl":"10.1155/2023/5797541","url":null,"abstract":"<div>\u0000 <p>BTKbase is an international database for disease-causing variants in Bruton tyrosine kinase (<i>BTK</i>) leading to X-linked agammaglobulinemia (XLA), a rare primary immunodeficiency of antibody production. BTKbase was established in 1994 as one of the first publicly available variation databases. The number of cases has more than doubled since the last update; it now contains information for 2310 DNA variants in 2291 individuals. 1025 of the DNA variants are unique. The human genome contains more than 500 protein kinases, among which BTK has the largest number of unique disease-causing variants. The current version of BTKbase has numerous novel features: the database has been reformatted, it has moved to LOVD database management system, it has been internally harmonized, etc. Systematics and standardization have been increased, including Variation Ontology annotations for variation types. There are some regions with lower than expected variation frequency and some hotspots for variations. BTKbase contains, in addition to variant descriptions at DNA, RNA and protein levels, also laboratory parameters and clinical features for many patients. BTKbase has served clinical and research communities in the diagnosis of XLA cases and provides general insight into effects of variations, especially in signalling pathways. Amino acid substitutions and their effects were investigated, predicted, and visualized at 3D level in the protein domains. BTKbase is freely available.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2023 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2023/5797541","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49472020","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}