Publications by authors named "Achille Iolascon"

211 Publications

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients.

Genes (Basel) 2021 Jun 23;12(7). Epub 2021 Jun 23.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy.

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). and were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance.
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http://dx.doi.org/10.3390/genes12070958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304671PMC
June 2021

The H159Y Variant Is Associated with Severe COVID-19: A Retrospective Study of 500 Patients from Southern Italy.

Genes (Basel) 2021 06 8;12(6). Epub 2021 Jun 8.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy.

To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.
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http://dx.doi.org/10.3390/genes12060881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226789PMC
June 2021

Regulatory Noncoding and Predicted Pathogenic Coding Variants of Predispose to Severe COVID-19.

Int J Mol Sci 2021 May 20;22(10). Epub 2021 May 20.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, Italy.

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting , can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level ( ≤ 1 × 10) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of .
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http://dx.doi.org/10.3390/ijms22105372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161088PMC
May 2021

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

J Public Health (Oxf) 2021 05 13. Epub 2021 May 13.

Centro di Coordinamento Malattie Rare, Regione Campania Naples 80131, Italy.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Results: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak.

Conclusions: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
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http://dx.doi.org/10.1093/pubmed/fdab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194710PMC
May 2021

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Acta Neuropathol Commun 2021 05 3;9(1):81. Epub 2021 May 3.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a Lyn showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.
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http://dx.doi.org/10.1186/s40478-021-01181-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091687PMC
May 2021

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model.

J Clin Invest 2021 May;131(10)

Department of Medicine, University of Verona, and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy.

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.
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http://dx.doi.org/10.1172/JCI144206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121526PMC
May 2021

Recommendations for pregnancy in Fanconi anemia.

Expert Opin Biol Ther 2021 Apr 12:1-7. Epub 2021 Apr 12.

Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

: Fanconi anemia (FA) is a rare congenital disease that belongs to the family of congenital trilinear bone marrow failure. Most FA patients will suffer bone marrow failure and the main treatment relies on supportive measures or more recently on the use of hematopoietic stem cell transplant. The improvements seen in the management of FA has led women to reach childbearing age and have successful pregnancies. However, these pregnancies are associated with increased complications such as preterm delivery, cesarean delivery, eclampsia and others.: This review highlights on the outcome of pregnancies in FA patients reported in the literature along with practical recommendations.: Multidisciplinary efforts are required to optimize the management of pregnancy in FA patients. Moreover, the development of a set of recommendations to optimize the treatment is highly necessary.
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http://dx.doi.org/10.1080/14712598.2021.1913119DOI Listing
April 2021

Common variants at 21q22.3 locus influence and gene expression and susceptibility to severe COVID-19.

iScience 2021 Apr 17;24(4):102322. Epub 2021 Mar 17.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples, Federico II, 80145 Naples, Italy.

The established risk factors of coronavirus disease 2019 (COVID-19) are advanced age, male sex, and comorbidities, but they do not fully explain the wide spectrum of disease manifestations. Genetic factors implicated in the host antiviral response provide for novel insights into its pathogenesis. We performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data, including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from the COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms within and near gene show associations with severe COVID-19. The minor alleles of the five single nucleotide polymorphisms (SNPs) correlated with a reduced risk of developing severe COVID-19 and high level of expression in blood. Our findings demonstrate that host genetic factors can influence the different clinical presentations of COVID-19 and that MX1 could be a potential therapeutic target.
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http://dx.doi.org/10.1016/j.isci.2021.102322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968217PMC
April 2021

Genetics and Genomics Approaches for Diagnosis and Research Into Hereditary Anemias.

Front Physiol 2020 22;11:613559. Epub 2020 Dec 22.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

The hereditary anemias are a relatively heterogeneous set of disorders that can show wide clinical and genetic heterogeneity, which often hampers correct clinical diagnosis. The classical diagnostic workflow for these conditions generally used to start with analysis of the family and personal histories, followed by biochemical and morphological evaluations, and ending with genetic testing. However, the diagnostic framework has changed more recently, and genetic testing is now a suitable approach for differential diagnosis of these patients. There are several approaches to this genetic testing, the choice of which depends on phenotyping, genetic heterogeneity, and gene size. For patients who show complete phenotyping, single-gene testing remains recommended. However, genetic analysis now includes next-generation sequencing, which is generally based on custom-designed targeting panels and whole-exome sequencing. The use of next-generation sequencing also allows the identification of new causative genes, and of polygenic conditions and genetic factors that modify disease severity of hereditary anemias. In the research field, whole-genome sequencing is useful for the identification of non-coding causative mutations, which might account for the disruption of transcriptional factor occupancy sites and regulatory elements. Moreover, advances in high-throughput sequencing techniques have now resulted in the identification of genome-wide profiling of the chromatin structures known as the topologically associating domains. These represent a recurrent disease mechanism that exposes genes to inappropriate regulatory elements, causing errors in gene expression. This review focuses on the challenges of diagnosis and research into hereditary anemias, with indications of both the advantages and disadvantages. Finally, we consider the future perspectives for the use of next-generation sequencing technologies in this era of precision medicine.
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http://dx.doi.org/10.3389/fphys.2020.613559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783452PMC
December 2020

A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma.

Front Oncol 2020 14;10:596191. Epub 2020 Dec 14.

CEINGE Biotecnologie Avanzate, Napoli, Italy.

Background: Liquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants with low allele frequency. Most retrospective studies conducted in small cohorts of pediatric cancers have illustrated that the technology yield substantial potential in neuroblastoma.

Aim: The molecular landscape of neuroblastoma harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to characterize the mutational landscape of primary neuroblastoma using a custom gene panel for ctDNA targeted sequencing.

Methods: Targeted next-generation sequencing (NGS) was performed on ctDNA of 11 patients with primary neuroblastoma stage 4. To avoid the detection of false variants, we used UMIs (unique molecular identifiers) for the library construction, increased the sequencing depth and developed bioinformatic analyses including the hard filtering of the variant calls.

Results: We identified 9/11 (81.8%) patients who carry at least one pathogenic variation. The most frequently mutated genes were (five cases), (four cases), (three cases), (three cases), (two cases), (two cases), (two cases) and (two cases).

Conclusions: We developed a targeted NGS approach to identify tumor-specific alterations in ctDNA of neuroblastoma patients. Our results show the reliability of our approach to generate genomic information which can be integrated with clinical and pathological data at diagnosis.
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http://dx.doi.org/10.3389/fonc.2020.596191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769379PMC
December 2020

RB1CC1 duplication and aberrant overexpression in a patient with schizophrenia: further phenotype delineation and proposal of a pathogenetic mechanism.

Mol Genet Genomic Med 2021 01 19;9(1):e1561. Epub 2020 Dec 19.

Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Background: Copy number variants in coding and noncoding genomic regions have been implicated as risk factor for schizophrenia (SCZ). Rare duplications of the RB1CC1 gene were found enriched in SCZ patients. Considering that the effect of such duplications on RB1CC1 expression has never been evaluated and partial gene duplications of RB1CC1 have also been reported in SCZ patients, it is unclear whether the pathogenesis is mediated by haploinsufficiency rather than genuine overexpression of the gene.

Methods And Results: We studied a patient with schizophrenia, suicidality, and obesity, who carried a de novo RB1CC1 complete duplication, as assessed by high-resolution array-CGH. Molecular breakpoint cloning allowed to identify nonhomologous end joining (NHEJ) as driving mechanism in this rearrangement. On the contrary, trio-based whole-exome sequencing excluded other potential causative variants related to the phenotype. Functional assays showed significant overexpression of RB1CC1 in the peripheral blood lymphocytes of the proband compared to control subjects, suggesting overdosage as leading mechanism in SCZ pathophysiology.

Conclusion: We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients.
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http://dx.doi.org/10.1002/mgg3.1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963413PMC
January 2021

Inherited microcytic anemias.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):465-470

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy; and.

Inherited microcytic anemias can be broadly classified into 3 subgroups: (1) defects in globin chains (hemoglobinopathies or thalassemias), (2) defects in heme synthesis, and (3) defects in iron availability or iron acquisition by the erythroid precursors. These conditions are characterized by a decreased availability of hemoglobin (Hb) components (globins, iron, and heme) that in turn causes a reduced Hb content in red cell precursors with subsequent delayed erythroid differentiation. Iron metabolism alterations remain central to the diagnosis of microcytic anemia, and, in general, the iron status has to be evaluated in cases of microcytosis. Besides the very common microcytic anemia due to acquired iron deficiency, a range of hereditary abnormalities that result in actual or functional iron deficiency are now being recognized. Atransferrinemia, DMT1 deficiency, ferroportin disease, and iron-refractory iron deficiency anemia are hereditary disorders due to iron metabolism abnormalities, some of which are associated with iron overload. Because causes of microcytosis other than iron deficiency should be considered, it is important to evaluate several other red blood cell and iron parameters in patients with a reduced mean corpuscular volume (MCV), including mean corpuscular hemoglobin, red blood cell distribution width, reticulocyte hemoglobin content, serum iron and serum ferritin levels, total iron-binding capacity, transferrin saturation, hemoglobin electrophoresis, and sometimes reticulocyte count. From the epidemiological perspective, hemoglobinopathies/thalassemias are the most common forms of hereditary microcytic anemia, ranging from inconsequential changes in MCV to severe anemia syndromes.
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http://dx.doi.org/10.1182/hematology.2020000158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727536PMC
December 2020

Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus.

Haematologica 2020 12 1;105(12):2883-2886. Epub 2020 Dec 1.

Dip. di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli Federico II, Napoli, Italy; CEINGE Biotecnologie Avanzate.

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http://dx.doi.org/10.3324/haematol.2020.258533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716369PMC
December 2020

Genetic Predisposition to Solid Pediatric Cancers.

Front Oncol 2020 28;10:590033. Epub 2020 Oct 28.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

Progresses over the past years have extensively improved our capacity to use genome-scale analyses-including high-density genotyping and exome and genome sequencing-to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.
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http://dx.doi.org/10.3389/fonc.2020.590033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656777PMC
October 2020

Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer.

ESMO Open 2020 09;5(5):e000753

Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Napoli, Campania, Italy. Electronic address:

Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab.

Methods: We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done.

Results: Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14-19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders.

Conclusion: Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC.EUDRACT 2017-004195-58.
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http://dx.doi.org/10.1136/esmoopen-2020-000753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484864PMC
September 2020

Recommendations for Pregnancy in Rare Inherited Anemias.

Hemasphere 2020 Aug 12;4(4):e446. Epub 2020 Aug 12.

United Onlus - Federazione Italiana delle Thalassemie, Emoglobinopatie Rare e Drepanocitosi, Ferrara, Italy.

Rare inherited anemias are a subset of anemias caused by a genetic defect along one of the several stages of erythropoiesis or in different cellular components that affect red blood cell integrity, and thus its lifespan. Due to their low prevalence, several complications on growth and development, and multi-organ system damage are not yet well defined. Moreover, during the last decade there has been a lack of proper understanding of the impact of rare anemias on maternal and fetal outcomes. In addition, there are no clear-cut guidelines outlining the pathophysiological trends and management options unique to this special population. Here, we present on behalf of the European Hematology Association, evidence- and consensus-based guidelines, established by an international group of experts in different fields, including hematologists, gynecologists, general practitioners, medical geneticists, and experts in rare inherited anemias from various European countries for standardized and appropriate choice of therapeutic interventions for the management of pregnancy in rare inherited anemias, including Diamond-Blackfan Anemia, Congenital Dyserythropoietic Anemias, Thalassemia, Sickle Cell Disease, Enzyme deficiency and Red cell membrane disorders.
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http://dx.doi.org/10.1097/HS9.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437563PMC
August 2020

Genetic Analysis of the Coronavirus SARS-CoV-2 Host Protease in Different Populations.

Front Genet 2020 4;11:872. Epub 2020 Aug 4.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples Federico II, Naples, Italy.

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http://dx.doi.org/10.3389/fgene.2020.00872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417663PMC
August 2020

Corrigendum: Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein.

Front Physiol 2020 11;11:940. Epub 2020 Aug 11.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

[This corrects the article DOI: 10.3389/fphys.2019.00621.].
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http://dx.doi.org/10.3389/fphys.2020.00940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432228PMC
August 2020

RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway.

Int J Mol Sci 2020 Aug 4;21(15). Epub 2020 Aug 4.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy.

Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in . Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of -silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these -silenced K562 cells with RAP-011, a "murinized" ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
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http://dx.doi.org/10.3390/ijms21155577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432210PMC
August 2020

Genetic counseling during COVID-19 pandemic: Tuscany experience.

Mol Genet Genomic Med 2020 10 3;8(10):e1433. Epub 2020 Aug 3.

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

Background: COVID-19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic.

Methods: We stratified all our scheduled visits, from March 9th through April 30th, and assessed case-by-case which genetic consultations should be maintained as face-to-face visit, or postponed/switched to telemedicine.

Results: Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face-to-face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow-up consultations: interestingly, 75% of our patients' parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection.

Conclusions: Spread of COVID-19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in-hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics.
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http://dx.doi.org/10.1002/mgg3.1433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435534PMC
October 2020

Uridine treatment normalizes the congenital dyserythropoietic anemia type II-like hematological phenotype in a patient with homozygous mutation in the CAD gene.

Am J Hematol 2020 11 19;95(11):1423-1426. Epub 2020 Aug 19.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

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http://dx.doi.org/10.1002/ajh.25946DOI Listing
November 2020

A novel PIEZO1 mutation in a patient with dehydrated hereditary stomatocytosis: a case report and a brief review of literature.

Ital J Pediatr 2020 Jul 23;46(1):102. Epub 2020 Jul 23.

Department of Pediatrics, "Lalla Seràgnoli," Hematology-Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 11, 40137, Bologna, Italy.

Background: Dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by hereditary hemolytic anemia.

Case Presentation: We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father.

Conclusions: This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.
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http://dx.doi.org/10.1186/s13052-020-00864-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379360PMC
July 2020

Congenital dyserythropoietic anemias.

Blood 2020 09;136(11):1274-1283

Department of Molecular Medicine and Medical Biotechnologies, "Federico II" University of Naples, Naples, Italy; and.

Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation-proliferation pathways of the erythroid lineage. They belong to the wide group of ineffective erythropoiesis conditions that mainly result in monolinear cytopenia. CDAs are classified into the 3 major types (I, II, III), plus the transcription factor-related CDAs, and the CDA variants, on the basis of the distinctive morphological, clinical, and genetic features. Next-generation sequencing has revolutionized the field of diagnosis of and research into CDAs, with reduced time to diagnosis, and ameliorated differential diagnosis in terms of identification of new causative/modifier genes and polygenic conditions. The main improvements regarding CDAs have been in the study of iron metabolism in CDAII. The erythroblast-derived hormone erythroferrone specifically inhibits hepcidin production, and its role in the mediation of hepatic iron overload has been dissected out. We discuss here the most recent advances in this field regarding the molecular genetics and pathogenic mechanisms of CDAs, through an analysis of the clinical and molecular classifications, and the complications and clinical management of patients. We summarize also the main cellular and animal models developed to date and the possible future therapies.
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http://dx.doi.org/10.1182/blood.2019000948DOI Listing
September 2020

19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis.

NPJ Genom Med 2020 15;5:18. Epub 2020 Apr 15.

1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.

Genomic aberrations of neuroblastoma occurring in late childhood and adolescence are still understudied. Publicly available DNA copy number profiles of 556 tumors (discovery set) and of 208 tumors obtained by array-CGH assay (validation set) were used to test if 19p loss is significantly over-represented in children and adolescents with neuroblastoma. The 19p loss occurrence was separately tested within different age groups in the discovery and validation set and the resulting values were combined by meta-analysis and corrected by Bonferroni's method. In both sets, 19p loss was associated with older age at diagnosis. Particularly, the lowest age group significantly associated with 19p loss (discovery set: 20%; validation set: 35%) was 6 years. The 19p loss correlated with inferior overall survival in patients over 6 years of age. Relevant tumor suppressor genes (, , and and microRNAs (miR-181c, miR-27a, and mirR-199a-1) are located in the genomic region involved in 19p loss. Downregulation of , and was associated with poor patient outcome and older age. Among the recurrent NB chromosomal aberrations, only 1q gain was enriched in patients older than 6, and its presence was mutually exclusive with respect to 19p loss. Our data demonstrate that 19p loss is a genomic biomarker of NB diagnosed in older children that can predict clinical outcome.
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http://dx.doi.org/10.1038/s41525-020-0125-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160145PMC
April 2020

Kinome multigenic panel identified novel druggable EPHB4-V871I somatic variant in high-risk neuroblastoma.

J Cell Mol Med 2020 06 26;24(11):6459-6471. Epub 2020 Apr 26.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

Neuroblastoma (NB) is the most common extracranial neoplasm in children. The overall outcome for high-risk NB patients is still unacceptable, therefore, it is critical to deeply understand molecular mechanisms associated with NB, which in turn can be utilized for developing drugs towards the treatment of NB. Protein kinases (TKs) play an essential role in the regulation of cell survival and proliferation. Different kinases, such as anaplastic lymphoma kinase (ALK), Aurora kinase, RET receptor tyrosine kinase, are potential therapeutic targets in various cancers, including NB. We analysed a cohort of 45 high-risk NB patients and 9 NB cell lines by a targeted-(t)NGS custom gene panel (genes codifying for the kinase domains of 90 TKs). We identified somatic variants in four TK genes (ALK, EPHB4, LMTK3 and EPHB6) in NB patients and we functionally characterized an interesting somatic variant, V871I, in EPHB4 gene. EPHB4 plays a crucial role in cardiovascular development and regulates vascularization in cancer-promoting angiogenesis, tumour growth and metastasis. Several EPHB4 mutations have previously been identified in solid and haematological tumour specimens but EPHB4 mutations were not described until now in NB. Interestingly, a re-analysis of public CGH-array showed that the EPHB4 gain is associated with advanced diseases in NB. We further demonstrated that higher EPHB4 expression is correlated to stage 4 of NB and with poor overall survival. Additionally, we also revealed that the EPHB4-V871I accounts for increased proliferation, migration and invasion properties in two NB cell lines by acting on VEGF, c-RAF and CDK4 target genes and by increasing the phosphorylation of ERK1-2 pathway. The use of two EPHB4 inhibitors, JI-101 and NVP-BHG712, was able to rescue the phenotype driven by the variant. Our study suggested that EPHB4 is a promising therapeutic target in high-risk NB.
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http://dx.doi.org/10.1111/jcmm.15297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294133PMC
June 2020

Bimodal strategy for excellent audiological rehabilitation in a subject with a novel nonsense mutation of the SLC26A4 gene: A case report.

Int J Pediatr Otorhinolaryngol 2020 Jul 24;134:110018. Epub 2020 Mar 24.

Institute of Audiology, Dept. of Neurosciences, Reproductive and Odontostomatologic Sciences, University of Naples Federico II, Naples, Italy; CEINGE- Advanced Biotechnologies, Naples, Italy. Electronic address:

Sensorineural hearing loss is a heterogeneous disease caused by mutations in many genes. However, in the presence of enlarged vestibular aqueduct, it is frequently associated with mutations in the solute carrier family 26 member 4 (SLC26A4), a gene causative of a syndromic form (Pendred) as well as a non-syndromic form of hearing loss (DFNB4). We describe a clinical case presenting bilateral sensorineural hearing loss and enlarged vestibular aqueduct in which a novel homozygous SLC26A4 mutation was identified. Despite a late diagnosis of hearing loss, a peculiar rehabilitation therapy strategy was identified that provided excellent results.
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http://dx.doi.org/10.1016/j.ijporl.2020.110018DOI Listing
July 2020

Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma.

J Cell Mol Med 2020 04 27;24(7):4072-4081. Epub 2020 Feb 27.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients' datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.
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http://dx.doi.org/10.1111/jcmm.15058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171401PMC
April 2020

Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma.

J Cancer 2020 14;11(6):1495-1504. Epub 2020 Jan 14.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

is associated with the development of high-risk neuroblastoma patients. Particularly, the expression of full length (FL) isoform, FL , correlates to high-risk neuroblastoma development and its inhibition is sufficient to induce neuroblastoma cells towards a worst phenotype. Here we have investigated the mechanisms of FL in neuroblastoma cell lines depleted for FL expression. We have shown that FL expression protects the cells from spontaneous DNA damage and from damage accumulated after irradiation. We demonstrated a role for FL as tumor suppressor to prevent unscheduled mitotic entry of DNA damaged cells and to lead to death cells that have bypassed cell cycle checkpoints. FL -depleted cells that have survived to checkpoints acquire features of aggressiveness. Overall, our results show that FL may defend cells against cancer and prevent malignant transformation of cells.
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http://dx.doi.org/10.7150/jca.36164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995383PMC
January 2020

Emerging drugs in randomized controlled trials for sickle cell disease: are we on the brink of a new era in research and treatment?

Expert Opin Investig Drugs 2020 Jan 25;29(1):23-31. Epub 2019 Dec 25.

Department of Medicine, University of Verona and AOUI Verona, Policlinico GB Rossi, Verona, Italy.

: Sickle cell disease (SCD) is caused by a mutation in the HBB gene which is key for making a component of hemoglobin. The mutation leads to the formation of an abnormal hemoglobin molecule called sickle hemoglobin (HbS). SCD is a chronic, complex disease with a multiplicity of pathophysiological targets; it has high morbidity and mortality.Hydroxyurea has for many years been the only approved drug for SCD; hence, the development of new therapeutics is critical.: This article offers an overview of the key studies of new therapeutic options for SCD. We searched the PubMed database and Cochrane Database of Systemic Reviews for agents in early phase clinic trials and preclinical development.: Although knowledge of SCD has progressed, patient survival and quality of life must be improved. Phase II and phase III clinical trials investigating pathophysiology-based novel agents show promising results in the clinical management of SCD acute events. The design of long-term clinical studies is necessary to fully understand the clinical impact of these new therapeutics on the natural history of the disease. Furthermore, the building of global collaborations will enhance the clinical management of SCD and the design of primary outcomes of future clinical trials.
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http://dx.doi.org/10.1080/13543784.2020.1703947DOI Listing
January 2020

A Novel εγδβ-Thalassemia Deletion Associated with Severe Anemia at Birth and a β-Thalassemia Intermedia Phenotype Later in Life in Three Generations of a Greek Family.

Hemoglobin 2019 Dec 12:1-4. Epub 2019 Dec 12.

Department of Molecular Medicine and Medical Biotechnology, CEINGE, Advanced Biotechnologies, University of Naples Federico II, Naples, Italy.

We describe a novel deletion causing heterozygous εγδβ-thalassemia (εγδβ-thal) across three generations of a Greek family. The Greek deletion is about 72 kb in length, spanning from the hypersensitive site 4 (HS4) in the locus control region (LCR) to the 3' end of the β-globin gene, thus encompassing the entire β-globin gene cluster. The deletion caused severe but transient neonatal anemia and a non transfusion-dependent chronic hemolytic anemia state later in life, resembling mild β-thalassemia intermedia (β-TI) rather than β-thalassemia (β-thal) trait, as had been previously reported. Apart from the presentation of clinical and laboratory characteristics, the challenges involving clinical management are also discussed.
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http://dx.doi.org/10.1080/03630269.2019.1699568DOI Listing
December 2019