Cold Spring Harbor Molecular Case Studies最新文献

{"title":"Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding.","authors":"Paul R Mark,&nbsp;Stephen A Murray,&nbsp;Tao Yang,&nbsp;Alexandra Eby,&nbsp;Angela Lai,&nbsp;Di Lu,&nbsp;Jacob Zieba,&nbsp;Surender Rajasekaran,&nbsp;Elizabeth A VanSickle,&nbsp;Linda Z Rossetti,&nbsp;Lucia Guidugli,&nbsp;Kelly Watkins,&nbsp;Meredith S Wright,&nbsp;Caleb P Bupp,&nbsp;Jeremy W Prokop","doi":"10.1101/mcs.a006169","DOIUrl":"https://doi.org/10.1101/mcs.a006169","url":null,"abstract":"<p><p>We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in <i>LRP1</i>, in which segregation analysis helped dismiss additional variants of interest. <i>LRP1</i> analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bf/b3/MCS006169Mar.PMC9632358.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10731786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive molecular characterization of a rare case of Philadelphia chromosome-positive acute myeloid leukemia.","authors":"Mara W Rosenberg,&nbsp;Samantha L Savage,&nbsp;Christopher A Eide,&nbsp;Anna Reister Schultz,&nbsp;Rachel J Cook,&nbsp;Richard D Press,&nbsp;Carole Rempfer,&nbsp;Garrett Eickelberg,&nbsp;Beth Wilmot,&nbsp;Shannon K McWeeney,&nbsp;Jeffrey W Tyner,&nbsp;Brian J Druker,&nbsp;Cristina E Tognon","doi":"10.1101/mcs.a006218","DOIUrl":"https://doi.org/10.1101/mcs.a006218","url":null,"abstract":"<p><p>The Philadelphia chromosome (Ph) resulting from the t(9;22) translocation generates the oncogenic BCR::ABL1 fusion protein that is most commonly associated with chronic myeloid leukemia (CML) and Ph-positive (Ph+) acute lymphoblastic leukemia (ALL). There are also rare instances of patients (≤1%) with newly diagnosed acute myeloid leukemia (AML) that harbor this translocation (Paietta et al., <i>Leukemia</i> <b>12:</b> 1881 [1998]; Keung et al., <i>Leuk Res</i> <b>28:</b> 579 [2004]; Soupir et al., <i>Am J Clin Pathol</i> <b>127:</b> 642 [2007]). AML with BCR::ABL has only recently been provisionally classified by the World Health Organization as a diagnostically distinct subtype of AML. Discernment from the extremely close differential diagnosis of myeloid blast crisis CML is challenging, largely relying on medical history rather than clinical characteristics (Arber et al., <i>Blood</i> <b>127:</b> 2391 [2016]). To gain insight into the genomic features underlying the evolution of AML with BCR::ABL, we identified a patient presenting with a high-risk myelodysplastic syndrome that acquired a BCR::ABL alteration after a peripheral blood stem cell transplant. Serial samples were collected and analyzed using whole-exome sequencing, RNA-seq, and ex vivo functional drug screens. Persistent subclones were identified, both at diagnosis and at relapse, including an <i>SF3B1</i>p.Lys700Glu mutation that later cooccurred with an <i>NRAS</i>p.Gly12Cys mutation. Functional ex vivo drug screening performed on primary patient cells suggested that combination therapies of ABL1 with RAS or PI3K pathway inhibitors could have augmented the patient's response throughout the course of disease. Together, our findings argue for the importance of genomic profiling and the potential value of ABL1 inhibitor-inclusive combination treatment strategies in patients with this rare disease.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/55/04/MCS006218Ros.PMC9632359.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9486583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Episodic ataxia type 2 (EA2) with interictal myokymia and focal dystonia.","authors":"Emilie Neerup Nielsen,&nbsp;Birna Ásbjörnsdóttir,&nbsp;Lisbeth Birk Møller,&nbsp;Jørgen Erik Nielsen,&nbsp;Suzanne Granhøj Lindquist","doi":"10.1101/mcs.a006236","DOIUrl":"https://doi.org/10.1101/mcs.a006236","url":null,"abstract":"<p><p>Episodic ataxia type 1 and 2 (EA1 and EA2) are the most well-described of the episodic ataxias. They are autosomal dominantly inherited early-onset diseases characterized by attacks of cerebellar dysfunction. EA1 is clinically characterized by short episodes of ataxia with interictal myokymia, whereas EA2 is characterized by longer-lasting recurrent ataxia, slurred speech, and interictal nystagmus. We report on a patient with EA2 with interictal focal dystonia and also interictal myokymia, which is hitherto not reported as an interictal feature associated to EA2. The patient carries a previously described heterozygous pathogenic de novo frameshift variant in the <i>CACNA1A</i> gene, establishing the diagnosis of EA2. She had symptom onset at age 13 and from age 48 she developed interictal myokymia and focal dystonia as illustrated in Supplemental Movie S1. We conclude that interictal myokymia and focal dystonia may be interictal features associated to EA2 caused by the cerebellar pathophysiology of EA2. Episodes of ataxia were successfully treated with acetazolamide in low dose, whereas the interictal features were unresponsive to acetazolamide.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e2/ef/MCS006236Nie.PMC9632360.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10633648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel large in-frame <i>FBN1</i> deletion causes neonatal Marfan syndrome.","authors":"Sümeyye Elgaz,&nbsp;Boris Wittekindt,&nbsp;Anoosh Esmaeili,&nbsp;Sebastian Fischer,&nbsp;Hanno J Bolz,&nbsp;Ulrich Zechner,&nbsp;Horst Buxmann","doi":"10.1101/mcs.a006213","DOIUrl":"https://doi.org/10.1101/mcs.a006213","url":null,"abstract":"<p><p>Neonatal Marfan syndrome (nMFS) is a rare and severe form of Marfan syndrome (MFS) with a poor prognosis, that presents with a highly variable phenotype, particularly regarding skeletal, ocular, and cardiovascular manifestations. Mutations in the fibrillin-1 (<i>FBN1</i>) gene are known as the principal cause of MFS and MFS-related syndromes. Here, we report on a full-term female neonate with postnatal characteristics suggestive of nMFS, including severe cardiovascular disease resulting in cardiorespiratory failure and death by 4 mo of age. We identified a novel large genomic in-frame deletion of <i>FBN1</i> exons 42-45, c.(5065 + 1_5066 - 1)_(5545 + 1_5546 - 1)del. Large <i>FBN1</i> in-frame deletions between exons 24 and 53 have been associated with severe MFS. The deletion in our patient differs from the <i>FBN1</i> region associated with the majority of nMFS cases, exons 24-32.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ac/2e/MCS006213Elg.PMC9632361.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10633651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and functional characterization of the oncogenicity and targetability of a novel <i>NOTCH1-ROS1</i> gene fusion in pediatric angiosarcoma.","authors":"Payal Jain,&nbsp;Sudarshan Iyer,&nbsp;Joshua Straka,&nbsp;Lea F Surrey,&nbsp;Jennifer Pogoriler,&nbsp;Harry Han,&nbsp;Tiffany Smith,&nbsp;Christine Busch,&nbsp;Elizabeth Fox,&nbsp;Marilyn Li,&nbsp;Angela J Waanders,&nbsp;Adam Resnick,&nbsp;Monika A Davare","doi":"10.1101/mcs.a006222","DOIUrl":"https://doi.org/10.1101/mcs.a006222","url":null,"abstract":"<p><p>Angiosarcomas are rare, malignant soft tissue tumors in children that arise in a wide range of anatomical locations and have limited targeted therapies available. Here, we report a rare case of a pediatric angiosarcoma (pAS) with Li-Fraumeni syndrome (LFS) expressing a novel <i>NOTCH1-ROS1</i> gene fusion. Although both <i>NOTCH1</i> and <i>ROS1</i> are established proto-oncogenes, our study is the first to describe the mechanistic role of <i>NOTCH1</i>-<i>ROS1</i> fusion arising via intrachromosomal rearrangement. NOTCH1-ROS1 displayed potent neoplastic transformation propensity in vitro, and harbors tumorigenic potential in vivo, where it induced oncogenic activation of the MAPK, PI3K/mTOR, and JAK-STAT signaling pathways in a murine allograft model. We found an unexpected contribution of the NOTCH1 extracellular region in mediating NOTCH1-ROS1 activation and oncogenic function, highlighting the contribution of both NOTCH1 and ROS1 fusion partners in driving tumorigenicity. Interestingly, neither membrane localization nor fusion protein dimerization were found to be essential for NOTCH1-ROS1 fusion oncogenicity. To target NOTCH1-ROS1-driven tumors, we tested both NOTCH1-directed inhibitors and ROS1-targeted tyrosine kinase inhibitors (TKI) in heterologous models (NIH3T3, Ba/F3). Although NOTCH1 inhibitors did not suppress NOTCH1-ROS1-driven oncogenic growth, we found that oral entrectinib treatment effectively suppressed the growth of NOTCH-ROS1-driven tumors. Taken together, we report the first known pAS case with a novel NOTCH1-ROS1 alteration along with a detailed report on the function and therapeutic targeting of NOTCH1-ROS1. Our study highlights the importance of genomic profiling of rare cancers such as pAS to reveal actionable drivers and improve patient outcomes.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"8 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d0/65/MCS006222Jai.PMC9632357.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9199659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia.","authors":"Fernando Freua, Mariana Espíndola de Castro Almeida, Paulo Ribeiro Nóbrega, Anderson Rodrigues Brandáo de Paiva, Bruno Della-Ripa, Paulina Cunha, Lúcia Inês Macedo-Souza, Clarissa Bueno, David S Lynch, Henry Houlden, Leandro Tavares Lucato, Fernando Kok","doi":"10.1101/mcs.a006232","DOIUrl":"10.1101/mcs.a006232","url":null,"abstract":"<p><strong>Introduction: </strong>Argininemia or arginase deficiency is a metabolic disorder caused by pathogenic variants in ARG1 and consists of a variable association of progressive spastic paraplegia, intellectual disability, and seizures. Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder characterized by lower limb spasticity. This study presents 7 patients with arginase 1 deficiency from 6 different families, all with an initial diagnosis of complicated HSP.</p><p><strong>Methods: </strong>We evaluated the clinical data of 7 patients belonging to six independent families who were diagnosed with hyperargininemia in a neurogenetics outpatient clinic.</p><p><strong>Results: </strong>All patients had lower limb spasticity and six had global developmental delay. Five individuals had intellectual disability and two had epilepsy. Psychiatric abnormalities were seen in two patients. In two participants of this study, MRI disclosed thinning of the corpus callosum. Molecular diagnosis was made by whole exome sequencing. All variants were present in homozygosis; we identified two novel missense variants, one novel frameshift variant, and one previously published missense variant.</p><p><strong>Discussion: </strong>Clinical diagnosis of early onset complicated hereditary spastic paraplegia was made in all patients. Two patients were initially suspected of having SPG11 due to thinning of the corpus callosum. As argininemia may present with a highly penetrant phenotype of spastic paraplegia associated with additional symptoms, this disease may represent a specific entity amongst the complicated HSPs.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/09/b3/MCS006232Fre.PMC9632362.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40386522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma.","authors":"Erin Butler, Lin Xu, Dinesh Rakheja, Blake Schwettmann, Shireen Toubbeh, Lei Guo, Jiwoon Kim, Stephen X Skapek, Yanbin Zheng","doi":"10.1101/mcs.a006190","DOIUrl":"10.1101/mcs.a006190","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is a childhood sarcoma composed of myoblast-like cells, which suggests a defect in terminal skeletal muscle differentiation. To explore potential defects in the differentiation program, we searched for mRNA splicing variants in genes encoding transcription factors driving skeletal muscle lineage commitment and differentiation. We studied two RMS cases and identified altered splicing resulting in \"skipping\" the second of three exons in MYOD1. RNA-Seq data from 42 tumors and additional RMS cell lines revealed exon 2 skipping in both MYOD1 and MYF5 but not in MYF6 or MYOG. Complementary molecular analysis of MYOD1 mRNA found evidence for exon skipping in 5 additional RMS cases. Functional studies showed that so-called MYODΔEx2 protein failed to robustly induce muscle-specific genes, and its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. In summary, we present previously unrecognized exon skipping within MYOD1 and MYF5 in RMS, and we propose that alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8f/ac/MCS006190But.PMC9528969.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40675150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Pathogenic CDH3 Variant underlying Heredity Hypotrichosis Simplex detected by Whole-Exome Sequencing (WES)-A Case Report.","authors":"Ayat Kadhi, Lamiaa Hamie, Christel Tamer, Georges Nemer, Mazen Kurban","doi":"10.1101/mcs.a006225","DOIUrl":"10.1101/mcs.a006225","url":null,"abstract":"<p><strong>Background: </strong>Heredity Hypotrichosis Simplex (HHS) is a rare non-syndromic disease form of Hypotrichosis Simplex (HS) characterized by progressive hair follicle (HF) miniaturization. It is usually inherited in an autosomal dominant manner. The differential diagnosis of HHS and the treatments remain challenging despite recent advancement. In this report, we describe a 19-year old female affected with HHS alongside most of her family members.</p><p><strong>Methods: </strong>Whole Exome Sequencing (WES) was performed for some of the family members to unravel the culprit gene involved in HHS phenotype and ascertain the dermatological examination that was done to classify the phenotypes of the disease.</p><p><strong>Results: </strong>A novel pathogenic variant in the CDH3 gene (p.Ser223GlyfsTer4) was identified as a plausible disease-causing variant for HHS.</p><p><strong>Conclusion: </strong>This is the first report to associate CDH3 variants with a HHS phenotype without macular degeneration using WES. WES is an important tool for genotype-phenotype correlation, precision in diagnosis, and in-depth understanding of the disease mechanisms, leading to possible novel therapeutic targets treatment and better patient's outcomes.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9528967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40610255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of a GLIS3 fusion in an infant with AML refractory to chemotherapy.","authors":"Stephen M Smith, Alex Lee, Schuyler Tong, Stanley Leung, Henry Hongo, Jose Rivera, Alejandro Sweet-Cordero, Jennifer Michlitsch, Elliot Stieglitz","doi":"10.1101/mcs.a006220","DOIUrl":"10.1101/mcs.a006220","url":null,"abstract":"<p><p>Infants diagnosed with acute myeloid leukemia (AML) frequently harbor cytogenetically cryptic fusions involving KMT2A, NUP98 or GLIS2. Those with AML driven specifically by CBFA2T3::GLIS2 fusions have a dismal prognosis and are currently risk-stratified to receive hematopoietic stem cell transplantation (HSCT) in first remission. Here we report an infant with AML who was refractory to multiple lines of chemotherapy but lacked an identifiable fusion despite cytogenetic, fluorescence in situ hybridization (FISH) and targeted next generation sequencing (NGS) testing. Research-grade RNASeq from a relapse sample revealed in-frame CBFA2T3::GLIS3 and GLIS3::CBFA2T3 fusions. A patient-derived xenograft (PDX) generated from this patient has a short latency period and represents a strategy to test novel agents that may be effective in this aggressive subtype of AML. This report describes the first case of AML with a CBFA2T3::GLIS3 fusion and highlights the need for unbiased NGS testing including RNASeq at diagnosis, as patients with CBFA2T3::GLIS3 fusions should be considered for HSCT in first remission.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ba/32/MCS006220Smi.PMC9528968.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40582146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PHIP variants associated with Chung-Jansen syndrome disrupt replication fork stability and genome integrity.","authors":"Neysha Tirado-Class, Caitlin Hathaway, Wendy K Chung, Huzefa Dungrawala","doi":"10.1101/mcs.a006212","DOIUrl":"10.1101/mcs.a006212","url":null,"abstract":"<p><p>Chung-Jansen syndrome (CJS) is a rare, autosomal dominant disorder characterized by developmental delay, intellectual disability/cognitive impairment, behavioral challenges, obesity, and dysmorphic features. CJS is associated with heterozygous variants in PHIP (Pleckstrin-Homology Interacting Protein), a gene that encodes one of several substrate receptors for Cullin4-RING (CRL4) E3 ubiquitin ligase complex. Full length PHIP, also called DCAF14, was recently identified to function as a replication stress response protein. Herein, we report the identification of two PHIP missense variants identified by exome sequencing in unrelated individuals with CJS. The variants p.D488V and p.E963G occur in different functional elements of DCAF14- WD40 repeat domain and pleckstrin homology-binding region (PBR), respectively. Using DNA fiber assays, we reveal that cells expressing either variant exhibit defective replication fork progression in conditions of replication stress. Furthermore, unlike wild type DCAF14, both variants fail to accomplish DNA replication after exposure to genotoxic stress indicating a critical role of DCAF14 in protecting stalled replication forks. Thus, we have identified replication defects associated with CJS variants and predict replication-associated genome instability with CJS syndrome.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/52/6a/MCS006212Tir.PMC9528965.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9223440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}