Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

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Whole exome sequencing in unclassified autoinflammatory diseases: more monogenic diseases in the pipeline?

Rheumatology ◽

10.1093/rheumatology/keaa165 ◽

2020 ◽

Author(s):

Can Kosukcu ◽

Ekim Z Taskiran ◽

Ezgi Deniz Batu ◽

Erdal Sag ◽

Yelda Bilginer ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Onset ◽

Cost Effective ◽

Bioinformatic Analysis ◽

Autoinflammatory Diseases ◽

Whole Exome ◽

Monogenic Diseases ◽

Strong Candidate ◽

Generation Sequencing

Abstract Objective Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). Methods Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. Results The median age at disease onset was 1.2 years (range 0.2–16) and at the time of study recruitment was 14 years (range 3.5–17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. Conclusion WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

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More prominent muscle involvement in patients with dermatomyositis with anti-Mi2 autoantibodies

Neurology ◽

10.1212/wnl.0000000000008443 ◽

2019 ◽

Vol 93 (19) ◽

pp. e1768-e1777 ◽

Cited By ~ 4

Author(s):

Iago Pinal-Fernandez ◽

Christopher A. Mecoli ◽

Maria Casal-Dominguez ◽

Katherine Pak ◽

Yuji Hosono ◽

...

Keyword(s):

Clinical Phenotype ◽

Disease Onset ◽

Muscle Disease ◽

Serum Samples ◽

Muscle Involvement ◽

Necrotizing Myopathy ◽

Immune Mediated ◽

Muscle Biopsies ◽

Immunosuppressant Treatment

ObjectiveTo define the clinical phenotype of dermatomyositis (DM) with anti-Mi2 autoantibodies.MethodsIn this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-Mi2–positive DM were compared to patients with anti-Mi2–negative DM, antisynthetase syndrome (AS), and immune-mediated necrotizing myopathy (IMNM). Longitudinal anti-Mi2 autoantibody titers were assessed.ResultsA total of 58 patients with anti-Mi2–positive DM, 143 patients with anti-Mi2–negative DM, 162 patients with AS, and 170 patients with IMNM were included. Among patients with anti-Mi2–positive DM, muscle weakness was present in 60% at disease onset and occurred in 98% during longitudinal follow-up; fewer patients with anti-Mi2–negative DM developed weakness (85%; p = 0.008). Patients with anti-Mi2–positive DM were weaker and had higher creatine kinase (CK) levels than patients with anti-Mi2–negative DM or patients with AS. Muscle biopsies from patients with anti-Mi2–positive DM had prominent necrosis. Anti-Mi2 autoantibody levels correlated with CK levels and strength (p < 0.001). With treatment, most patients with anti-Mi2–positive DM had improved strength and CK levels; among 10 with multiple serum samples collected over 4 or more years, anti-Mi2 autoantibody titers declined in all and normalized in 3, 2 of whom stopped immunosuppressant treatment and never relapsed. Patients with anti-Mi2–positive DM had less calcinosis (9% vs 28%; p = 0.003), interstitial lung disease (5% vs 16%; p = 0.04), and fever (7% vs 21%; p = 0.02) than did patients with anti-Mi2–negative DM.ConclusionsPatients with anti-Mi2–positive DM have more severe muscle disease than patients with anti-Mi2–negative DM or patients with AS. Anti-Mi2 autoantibody levels correlate with disease severity and may normalize in patients who enter remission.

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THU0351 MUSCLE INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS AND ANTI-PM/SCL+ ANTIBODIES IS ASSOCIATED WITH CARDIAC AND PULMONARY INVOLVEMENT. ANALYSIS OF THE MULTICENTRE EUSTAR COHORT.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3525 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 407.1-407

Author(s):

M. G. Lazzaroni ◽

S. Zingarelli ◽

P. Airò ◽

Y. Allanore ◽

O. Distler

Keyword(s):

Systemic Sclerosis ◽

Cardiac Involvement ◽

Severe Disease ◽

Disease Onset ◽

Pulmonary Involvement ◽

Left Ventricular ◽

Research Support ◽

Muscle Involvement ◽

Group A ◽

Tendon Friction Rubs

Background:Anti-PM/Scl antibodies positivity has been associated with frequent skeletal muscle involvement in patients with Systemic Sclerosis (SSc) in different studies, including the EUSTAR cohort (1). Moreover, although myositis has been previously associated with heart involvement in SSc patients (2), this issue has never been explored among anti-PM/Scl+ patients.Objectives:To evaluate the cardiac involvement in anti-PM/Scl patients with SSc in the large multicentre EUSTAR database, with focus on the subgroup of patients with muscle involvement.Methods:Patients from the EUSTAR database were included when the item anti-PM/Scl was fulfilled in at least one visit.Results:Anti-PM/Scl status was available in 7,353 SSc patients from EUSTAR database: 295 were anti-PM/Scl+. After exclusion of 151 patients with multiple autoantibody positivity, 144 anti-PM/Scl + patients were compared with 7,058 anti-PM/Scl- patients. Among them, 3,120 (44.2%) were positive for ACA, 2,361 (33.5%) for anti-Topo I and 274 (3.88%) for anti-RNAP3.Regarding the specific cardiac outcomes, in the anti-PM/Scl+ as compared to the anti-PM/Scl- group, a decreased rate of elevated sPAP at ECHO was recorded (12.8% vs 25.0%, p:0.001), while no differences were observed in the frequency of conduction blocks (26.2% vs 23.7%, p:0.526), abnormal diastolic function (33.9% vs 36.4%, p:0.582), pericardial effusion (10.2% vs 10.9%, p:1.000) and LVEF ≤50% (4.76% vs 6.11%, p:0.818). In multivariate analysis, adjusted for age at disease onset, sex, and disease duration, the negative association of anti-PM/Scl with elevated sPAP was not confirmed (p:0.061).When comparing anti-PM/Scl+ patients with (n=47) and without (n=87) CK elevation, the former group had a higher frequency of conduction blocks (43.2% vs 17.5%, p:0.005; OR 95% CI 3.47, 1.51-7.97) and left ventricular dysfunction, both diastolic (45.6% vs 27.2%, p:0.050; OR 95% CI 2.25, 1.05-4.81) and systolic (LVEF ≤50% 13.3% vs 0%, p:0.018; OR 95% CI 16.8, 0.87-324). Moreover, anti-PM/Scl+ patients with CK elevation had significantly increased rate of lung fibrosis on HRCT (p:0.045), intestinal symptoms (p:0.017), joint contractures (p:0.045) and tendon friction rubs (p:0.034).Conclusion:In the largest series of anti-PM/Scl positive SSc patients so far reported, muscle involvement in anti-PM/Scl+ patients (defined as increased serum CK) seems to represent a marker of a more severe disease phenotype, including a higher frequency of cardio-pulmonary involvement.References:[1]Lazzaroni MG, et al. Ann Rheum Dis 2018. 77 (2), 421-2.[2]Follansbee WP, et al. Am Heart J 1993. 125: 194-203.Acknowledgments:Authors would like to thank the patients’ association GILS (Gruppo Italiano Lotta Sclerodermia) for the grant that supported the project.Disclosure of Interests:Maria Grazia Lazzaroni: None declared, Stefania Zingarelli: None declared, Paolo Airò: None declared, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

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Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01986-8 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Marta Codrich ◽

Emiliano Dalla ◽

Catia Mio ◽

Giulia Antoniali ◽

Matilde Clarissa Malfatti ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Cell Model ◽

Patient Specific ◽

Driver Genes ◽

Proteomic Data ◽

Whole Exome ◽

Molecular Stability ◽

Culturing Conditions ◽

Colorectal Cancer Progression

Abstract Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. Methods Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. Results Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients’ tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification. Conclusion The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient’s tumor, underlining relevant potentialities of this 3D model.

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Small-Area Analysis of Incidence and Localisation of Vulvar Cancer

Journal of Oncology ◽

10.1155/2010/512032 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Klaus H. Baumann ◽

Olga Müller ◽

Helke B. Naujok ◽

Ellen Mann ◽

Peter Barth ◽

...

Keyword(s):

Older Women ◽

Small Area ◽

Vulvar Cancer ◽

Disease Onset ◽

University Hospital ◽

Hospital Unit ◽

Local Extension ◽

Disease Characteristics ◽

Recent Developments ◽

Rising Incidence

Objective. Vulvar cancer is a rare disease mainly in older women. HPV and non-HPV induced vulvar cancer reflect two types of oncogenesis. Controversies exist on most recent developments in vulvar cancer incidence, patients, and disease characteristics. Changes in incidence, age of disease onset, and tumor site in women treated for primary vulvar cancer in a single German university hospital unit will be described.Methods. A retrospective analysis of patient records of women treated between 1994 and 2008 was performed. The fifteen-year-spanning period was divided into three five year-spanning cohorts. Descriptive and statistical analyses were performed.Results. 104 patients were identified: cohort-1 from 1994 to 1998 (11 patients); cohort-2 from 1999 to 2003 (21 patients); cohort-3 from 2004 to 2008 (72 patients). Mean age (years) was 73.18 (confidence interval (CI): 64.04; 82.33), 58.9 (CI: 52.24; 65.57), and 61.19 (CI: 57.27; 65.12), respectively. Vulvar cancer confined to the region between clitoris and urethra was seen more often in cohort-3 () compared to cohort-1 () or cohort-2 ().Conclusion. This analysis supports the notion of rising incidence of vulvar cancer and a changing pattern of anatomical local extension. Disease onset is not restricted to older women.

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Comparing Five Year Out-Come in Two Cohorts of Patients with Early Rheumatoid Arthritis – A BARFOT Study

The Open Rheumatology Journal ◽

10.2174/1874312901409010008 ◽

2015 ◽

Vol 9 (1) ◽

pp. 8-15 ◽

Cited By ~ 13

Author(s):

Maria L.E Andersson ◽

Kristina Forslind ◽

Ingiäld Hafström

Keyword(s):

Prospective Observational Study ◽

Disease Activity Score ◽

Disease Duration ◽

Disease Onset ◽

Health Assessment ◽

Disease Characteristics ◽

Group 2 ◽

Assessment Questionnaire ◽

Group 1

The objective of the study was to compare disease characteristics over the first 5 years of disease in patients with RA, with disease onset in 1990s and 2000s, respectively. Methods : All 2235 patients with early RA (disease duration ≤12 months) were recruited from the BARFOT prospective observational study. These patients were divided into group 1 included 1992 to 1999 (N=1084, 66% women) and group 2 included 2000 to 2006 (N=1151, 69% women). Disease Activity Score (DAS28), VAS pain and Health Assessment Questionnaire (HAQ) were assessed during 5 years. Remission was defined as DAS28 <2.6. Results : At inclusion, both women and men in group 2 had higher mean DAS28 (SD) than group 1, 5.42 (1.22) vs 5.26 (1.19), p=0.004 and 5.28 (1.22) vs 5.00 (1.27), p=0.004, respectively, mainly dependant on pain and not on inflammatory related measures. Over time DAS28 decreased and was in both genders, from 6 months to the 5-year follow-up, significantly lower in group 2. At 5-year, both women and men in group 2 had higher rate of remission than women and men in group 1. However, despite reduction of VAS pain and HAQ there were no differences in pain and HAQ between groups at any time point. Conclusion : Patients included in the 2000s achieved higher frequency of remission at the 5 year follow-up compared with those included in the 1990s, suggested to reflect the more active medical treatment. Interestingly, however, improvement in pain and HAQ did not differ between the two patient cohorts.

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Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

Neuropediatrics ◽

10.1055/s-0038-1668141 ◽

2018 ◽

Vol 49 (06) ◽

pp. 379-384 ◽

Cited By ~ 7

Author(s):

Kerstin Becker ◽

Peter Herkenrath ◽

Christoph Düchting ◽

Friederike Körber ◽

Pablo Landgraf ◽

...

Keyword(s):

Autosomal Dominant ◽

Index Patient ◽

Speech Development ◽

Episodic Ataxia ◽

Cerebellar Hemisphere ◽

First Episode ◽

Whole Exome ◽

Neurologic Disorders ◽

Left Cerebellar Hemisphere ◽

Impaired Speech

AbstractMutations in SCN2A are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by SCN2A-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in SCN2A (NM_021007, c.4949T > C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of SCN2A-associated neurologic disorders, emphasizing that SCN2A mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.

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Mining cancer biology through bioinformatic analysis of proteomic data

Expert Review of Proteomics ◽

10.1080/14789450.2019.1654862 ◽

2019 ◽

Vol 16 (9) ◽

pp. 733-747

Author(s):

Marcello Manfredi ◽

Jessica Brandi ◽

Claudia Di Carlo ◽

Virginia Vita Vanella ◽

Elettra Barberis ◽

...

Keyword(s):

Cancer Biology ◽

Bioinformatic Analysis ◽

Proteomic Data

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Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation

Neural Plasticity ◽

10.1155/2020/8829587 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xiuhua Chao ◽

Yun Xiao ◽

Fengguo Zhang ◽

Jianfen Luo ◽

Ruijie Wang ◽

...

Keyword(s):

Hearing Loss ◽

Cochlear Implantation ◽

Novel Mutation ◽

Clinical Manifestations ◽

Bioinformatic Analysis ◽

Chinese Family ◽

Whole Exome ◽

Novel Variant ◽

Genetic Features ◽

The Right

Aims. This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods. A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results. A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion. A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

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Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽

10.3390/genes10121047 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1047 ◽

Cited By ~ 1

Author(s):

Lama Jaffal ◽

Wissam H Joumaa ◽

Alexandre Assi ◽

Charles Helou ◽

George Cherfan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Usher Syndrome ◽

Bioinformatic Analysis ◽

Next Generation ◽

Novel Mutations ◽

Pathogenic Variants ◽

Whole Exome ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

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