Publications by authors named "Raffaella Cascella"

44 Publications

Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders.

J Pers Med 2021 May 26;11(6). Epub 2021 May 26.

Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy.

Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11060474DOI Listing
May 2021

Multi-Layer Picture of Neurodegenerative Diseases: Lessons from the Use of Big Data through Artificial Intelligence.

J Pers Med 2021 Apr 7;11(4). Epub 2021 Apr 7.

IRCCS Santa Lucia Foundation, Genomic Medicine Laboratory UILDM, 00179 Rome, Italy.

In the big data era, artificial intelligence techniques have been applied to tackle traditional issues in the study of neurodegenerative diseases. Despite the progress made in understanding the complex (epi)genetics signatures underlying neurodegenerative disorders, performing early diagnosis and developing drug repurposing strategies remain serious challenges for such conditions. In this context, the integration of multi-omics, neuroimaging, and electronic health records data can be exploited using deep learning methods to provide the most accurate representation of patients possible. Deep learning allows researchers to find multi-modal biomarkers to develop more effective and personalized treatments, early diagnosis tools, as well as useful information for drug discovering and repurposing in neurodegenerative pathologies. In this review, we will describe how relevant studies have been able to demonstrate the potential of deep learning to enhance the knowledge of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases through the integration of all sources of biomedical data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11040280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067806PMC
April 2021

Comparative analysis of antigen and molecular tests for the detection of Sars-CoV-2 and related variants: A study on 4266 samples.

Int J Infect Dis 2021 Apr 18;108:187-189. Epub 2021 Apr 18.

Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy; Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, 00179 Rome, Italy. Electronic address:

Objectives: The present study compared the performance of the Lumipulse G Sars-CoV-2 Ag kit with the TaqPath COVID-19 RT-PCR CE IVD kit.

Methods: The study was conducted on 4266 naso-oropharyngeal swabs. Samples were subjected to antigen RT-PCR tests for the detection of Sars-CoV-2 and related variants. Statistical analyses were conducted in R software.

Results: We found 503 positives (including 138 H69-V70 deletion carriers) and 3763 negatives by RT-PCR, whereas 538 positives and 3728 negatives were obtained by antigen testing. We achieved empirical and binormal AU-ROCs of 0.920 and 0.990, accuracy of 0.960, sensitivity of 0.866, specificity of 0.973, positive and negative predictive values of 0.810 and 0.980. We obtained a positive correlation between viral loads and antigen levels (R = 0.81), finding a complete concordance for high viral loads (log copies/mL > 5.4). Antigen levels > 222 pg/mL were found to be reliable in assigning positive samples (p < 0.01). Concerning variant carriers, antigen test detected them with the same accuracy as other positive samples.

Conclusions: Molecular and antigen tests should be evaluated regarding the prevalence of the area. In case of low prevalence, antigen testing can be employed as a first-line screening for the timely identification of affected individuals with high viral load, also if carriers of Sars-CoV-2 variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053214PMC
April 2021

Genetic Variants Allegedly Linked to Antisocial Behaviour Are Equally Distributed Across Different Populations.

J Pers Med 2021 Mar 16;11(3). Epub 2021 Mar 16.

Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy.

Human behaviour is determined by a complex interaction of genetic and environmental factors. Several studies have demonstrated different associations between human behaviour and numerous genetic variants. In particular, allelic variants in SLC6A4, MAOA, DRD4, and DRD2 showed statistical associations with major depressive disorder, antisocial behaviour, schizophrenia, and bipolar disorder; BDNF polymorphic variants were associated with depressive, bipolar, and schizophrenia diseases, and TPH2 variants were found both in people with unipolar depression and in children with attention deficit-hyperactivity disorder (ADHD). Independent studies have failed to confirm polymorphic variants associated with criminal and aggressive behaviour. In the present study, a set of genetic variants involved in serotoninergic, dopaminergic, and neurobiological pathways were selected from those previously associated with criminal behaviour. The distribution of these genetic variants was compared across worldwide populations. While data on single polymorphic variants showed differential distribution across populations, these differences failed to be significant when a comprehensive analysis was conducted on the total number of published variants. The lack of reproducibility of the genetic association data published to date, the weakness of statistical associations, the heterogeneity of the phenotype, and the massive influence of the environment on human behaviour do not allow us to consider these genetic variants as undoubtedly associated with antisocial behaviour. Moreover, these data confirm the absence of ethnic predisposition to aggressive and criminal behaviour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11030213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002417PMC
March 2021

Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy.

Cell Death Differ 2021 Mar 15. Epub 2021 Mar 15.

IRCCS Fondazione Santa Lucia, Rome, Italy.

The role of mitophagy, a process that allows the removal of damaged mitochondria from cells, remains unknown in multiple sclerosis (MS), a disease that is found associated with dysfunctional mitochondria. Here we have qualitatively and quantitatively studied the main players in PINK1-mediated mitophagy in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting MS. We found the variant c.491G>A (rs550510, p.G140E) of NDP52, one of the major mitophagy receptor genes, associated with a MS cohort. Through the characterization of this variant, we discovered that the residue 140 of human NDP52 is a crucial modulator of NDP52/LC3C binding, promoting the formation of autophagosomes in order to drive efficient mitophagy. In addition, we found that in the PBMC population, NDP52 is mainly expressed in B cells and by ensuring efficient mitophagy, it is able to limit the production of the proinflammatory cytokine TNF-α following cell stimulation. In sum, our results contribute to a better understanding of the role of NDP52 in mitophagy and underline, for the first time, a possible role of NDP52 in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41418-021-00766-3DOI Listing
March 2021

Investigation of Genetic Variations of and as Potential Prognostic and Pharmacogenetics Biomarkers: Implications for COVID-19 and Neuroinflammatory Disorders.

Life (Basel) 2020 Dec 16;10(12). Epub 2020 Dec 16.

Genomic Medicine Laboratory, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.

In the present study, we investigated the distribution of genetic variations in and genes, which may be employed as prognostic and pharmacogenetic biomarkers for COVID-19 and neurodegenerative diseases. The study was performed on 271 samples representative of the Italian general population and identified seven variants (rs140764737, rs142164099, rs2069849, rs142759801, rs190436077, rs148171375, rs13306435) in and five variants (rs2228144, rs2229237, rs2228145, rs28730735, rs143810642) within , respectively. These variants have been predicted to affect the expression and binding ability of IL6 and IL6R. Ingenuity Pathway Analysis (IPA) showed that IL6 and IL6R appeared to be implicated in several pathogenetic mechanisms associated with COVID-19 severity and mortality as well as with neurodegenerative diseases mediated by neuroinflammation. Thus, the availability of --related biomarkers for COVID-19 may be helpful to counteract harmful complications and prevent multiorgan failure. At the same time, --related biomarkers could also be useful for assessing the susceptibility and progression of neuroinflammatory disorders and undertake the most suitable treatment strategies to improve patients' prognosis and quality of life. In conclusion, this study showed how IL6 pleiotropic activity could be exploited to meet different clinical needs and realize personalized medicine protocols for chronic, age-related and modern public health emergencies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/life10120351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765585PMC
December 2020

Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes.

J Cell Mol Med 2020 12 31;24(23):13554-13563. Epub 2020 Oct 31.

Medical Genetics Laboratory, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.

Psoriasis and psoriatic arthritis are multifactorial chronic disorders whose etiopathogenesis essentially derives from the alteration of several signalling pathways and the co-occurrence of genetic, epigenetic and non-genetic susceptibility factors that altogether affect the functional and structural property of the skin. Although shared and differential susceptibility genes and molecular pathways are known to contribute to the onset of pathological phenotypes, further research is needed to dissect the molecular causes of psoriatic disease and its progression towards Psoriatic Arthritis. This review will therefore be addressed to explore differences and similarities in the etiopathogenesis and progression of both disorders, with a particular focus on genes involved in the maintenance of the skin structure and integrity (keratins and collagens), modulation of patterns of recognition (through Toll-like receptors and dectin-1) and immuno-inflammatory response (by NLRP3-dependent inflammasome) to microbial pathogens. In addition, special emphasis will be given to the contribution of epigenetic elements (methylation pattern, non-coding RNAs, chromatin modifiers and 3D genome organization) to the etiopathogenesis and progression of psoriasis and psoriatic arthritis. The evidence discussed in this review highlights how the knowledge of patients' clinical and (epi)genomic make-up could be helpful for improving the available therapeutic strategies for psoriasis and psoriatic arthritis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.15742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754002PMC
December 2020

A Novel Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn's Disease.

Biomedicines 2020 Jul 22;8(8). Epub 2020 Jul 22.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn's disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7.

Methods: rs144204026 SNP frequency was evaluated in two independent Italian cohorts of Crohn's disease patients and normal controls. Genotyping was performed by allelic discrimination assay. expression was evaluated in or heterozygous PBMCs treated with Smad7 AS.

Results: No TT genotype was seen in CD patients and controls. Heterozygous genotype was more frequent in CD patients of both cohort 1 (11/235, 4.68%) and cohort 2 (8/122, 6.56%) as compared to controls (6/363, 1.65%; = 0.029 and = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients' susceptibility ( = 0.008; OR = 3.28, 95%CI: 1.3-8.3). Smad7 AS down-regulated RNA independently of the presence of the variant allele.

Conclusions: This is the first study to show an association between rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8080234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460430PMC
July 2020

Analysis of Genetic Variability among Populations Highlights a Possible Link with COVID-19-Related Neurological Complications.

Genes (Basel) 2020 07 3;11(7). Epub 2020 Jul 3.

Medical Genetics Laboratory, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy.

Angiotensin-converting enzyme 2 (ACE2) has been recognized as the entry receptor of the novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Structural and sequence variants in gene may affect its expression in different tissues and determine a differential response to SARS-Cov-2 infection and the COVID-19-related phenotype. The present study investigated the genetic variability of in terms of single nucleotide variants (SNVs), copy number variations (CNVs), and expression quantitative loci (eQTLs) in a cohort of 268 individuals representative of the general Italian population. The analysis identified five SNVs (rs35803318, rs41303171, rs774469453, rs773676270, and rs2285666) in the Italian cohort. Of them, rs35803318 and rs2285666 displayed a significant different frequency distribution in the Italian population with respect to worldwide population. The eQTLs analysis located in and targeting revealed a high distribution of eQTL variants in different brain tissues, suggesting a possible link between genetic variability and the neurological complications in patients with COVID-19. Further research is needed to clarify the possible relationship between expression and the susceptibility to neurological complications in patients with COVID-19. In fact, patients at higher risk of neurological involvement may need different monitoring and treatment strategies in order to prevent severe, permanent brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11070741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397291PMC
July 2020

Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.

World J Diabetes 2020 May;11(5):155-164

Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy.

The progressive aging of populations has resulted in an increased prevalence of chronic pathologies, especially of metabolic, neurodegenerative and movement disorders. In particular, type 2 diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most prevalent age-related, multifactorial pathologies that deserve particular attention, given their dramatic impact on patient quality of life, their economic and social burden as well the etiopathogenetic mechanisms, which may overlap in some cases. Indeed, the existence of common triggering factors reflects the contribution of mutual genetic, epigenetic and environmental features in the etiopathogenetic mechanisms underlying T2D and AD/PD. On this subject, this review will summarize the shared (epi)genomic features that characterize these complex pathologies. In particular, genetic variants and gene expression profiles associated with T2D and AD/PD will be discussed as possible contributors to determine the susceptibility and progression to these disorders. Moreover, potential shared epigenetic modifications and factors among T2D, AD and PD will also be illustrated. Overall, this review shows that findings from genomic studies still deserves further research to evaluate and identify genetic factors that directly contribute to the shared etiopathogenesis. Moreover, a common epigenetic background still needs to be investigated and characterized. The evidences discussed in this review underline the importance of integrating large-scale (epi)genomic data with additional molecular information and clinical and social background in order to finely dissect the complex etiopathogenic networks that build up the "disease interactome" characterizing T2D, AD and PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4239/wjd.v11.i5.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243483PMC
May 2020

Genetic Counseling and NGS Screening for Recessive LGMD2A Families.

High Throughput 2020 May 10;9(2). Epub 2020 May 10.

Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, 00179 Rome, Italy.

Genetic counseling applied to limb-girdle muscular dystrophies (LGMDs) can be very challenging due to their clinical and genetic heterogeneity and the availability of different molecular assays. Genetic counseling should therefore be addressed to select the most suitable approach to increase the diagnostic rate and provide an accurate estimation of recurrence risk. This is particularly true for families with a positive history for recessive LGMD, in which the presence of a known pathogenetic mutation segregating within the family may not be enough to exclude the risk of having affected children without exploring the genetic background of phenotypically unaffected partners. In this work, we presented a family with a positive history for LGMD2A (OMIM #253600, also known as calpainopathy) characterized by compound heterozygosity for two mutations. The genetic specialist suggested the segregation analysis of both mutations within the family as a first-level analysis. Sequentially, next-generation sequencing (NGS) analysis was performed in the partners of healthy carriers to provide an accurate recurrence/reproductive risk estimation considering the genetic background of the couple. Finally, this work highlighted the importance of providing a genetic counseling/testing service even in unaffected individuals with a carrier partner. This approach can support genetic counselors in estimating the reproductive/recurrence risk and eventually, suggesting prenatal testing, early diagnosis or other medical surveillance strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ht9020013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349198PMC
May 2020

RNAseq-Based Prioritization Revealed , , and as Common and Differential Susceptibility Biomarkers for Psoriasis and Psoriatic Arthritis: Confirmation from Genotyping Analysis of 1417 Italian Subjects.

Int J Mol Sci 2020 Apr 15;21(8). Epub 2020 Apr 15.

Medical Genetics Laboratory, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy.

Psoriasis (Ps) and Psoriatic Arthritis (PsA) are characterized by a multifactorial etiology, involving genetic and environmental factors. The present study aimed to investigate polymorphisms (SNPs) within genes involved in extracellular matrix and cell homeostasis and microRNA genes as susceptibility biomarkers for Ps and PsA. Bioinformatic analysis on public RNA-seq data allowed for selection of rs12488457 (A/C, ), rs13081855 (G/T, ), rs3812111 (A/T, ) and rs2910164 (C/G, ) as candidate biomarkers. These polymorphisms were analyzed by Real-Time PCR in a cohort of 1417 Italian patients (393 Ps, 424 PsA, 600 controls). Statistical and bioinformatic tools were utilized for assessing the genetic association and predicting the effects of the selected SNPs. rs12488457, rs13081855 and rs2910164 were significantly associated with both Ps ( = 1.39 × 10, = 4.52 × 10, = 0.04, respectively) and PsA ( = 5.12 × 10, = 1.19 × 10, = 0.01, respectively). rs3812111, instead, was associated only with PsA ( = 0.005). Bioinformatic analysis revealed common and differential biological pathways involved in Ps and PsA. and take part in the proliferation and angiogenic pathways which are altered in Ps/PsA and contribute to inflammation together with . On the other hand, the exclusive association of with PsA highlighted the specific involvement of bone metabolism in PsA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21082740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215451PMC
April 2020

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.

Biochim Biophys Acta Mol Basis Dis 2020 07 8;1866(7):165793. Epub 2020 Apr 8.

Dept of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2020.165793DOI Listing
July 2020

NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in Gene.

Genes (Basel) 2019 10 12;10(10). Epub 2019 Oct 12.

Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy.

This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The proband was subjected to NGS, utilizing a customized panel including 24 genes associated with RP and other retinal dystrophies. The NGS analysis revealed a novel missense variant (c.668T > A, I223N) in gene, which was investigated by segregation and bioinformatic analysis. The variant is located in the D2 loop domain of PRPH2, which is critical for protein activity. Bioinformatic analysis described the c.668T > A as a likely pathogenic variant. Moreover, a 3D model prediction was performed to better characterize the impact of the variant on the protein, reporting a disruption of the α-helical structures. As a result, the variant protein showed a substantially different conformation with respect to the wild-type PRPH2. The identified variant may therefore affect the oligomerization ability of the D2 loop and, ultimately, hamper PRPH2 proper functioning and localization. In conclusion, _c.668T > A provided a molecular explanation of RP symptomatology, highlighting the clinical utility of NGS panels to facilitate genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes10100792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826621PMC
October 2019

The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.

Hum Mol Genet 2019 12;28(23):3912-3920

Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy.

In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1-7 RU, borderline: 8-10RU and normal fragment: >11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3'untranslated region (3'UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs*48), c.2129dupC (p.A711Cfs*11), c.3469G>T (p.G1157*), c.5150_5151delAA (p.K1717Rfs*16) and c.1131+2_1131+5delTAAG, c.3010A>T (p.K1004*), c.853G>C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.*1376A>C, rs7238459; c.*1579G>A, rs559994; c.*1397A>G, rs150573037; c.*1631C>T, rs193227855; c.*1889G>C, rs149259359) were identified in the 3'UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddz239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969370PMC
December 2019

Atopic Eczema: Genetic Analysis of , , and in Mediterranean Populations.

Biomed Res Int 2019 4;2019:3457898. Epub 2019 Jun 4.

Department of Biomedicine and Prevention, Tor Vergata University, via Montpellier 1, 00133, Rome, Italy.

To date, the genes associated with susceptibility to Atopic Eczema (AE) are mainly implicated in immunity, inflammation, and maintenance of skin barrier. Little is known about the possible relationship between genes modulating Extra-Cellular Matrix (ECM) and AE etiopathogenesis. In this regard, the primary objective of the present study has been the investigation of susceptibility biomarkers localized within genes encoding collagen proteins. Several studies have shown that polymorphisms within the genes encoding such proteins may generate abnormal connective tissues, making them more susceptible to mechanical stress, loss of epidermal integrity, and aging. We therefore decided to investigate three polymorphisms located in , and as potential susceptibility biomarkers for AE in a cohort of 1470 subjects of Mediterranean origin. The genes of interest have been selected considering that the ECM and immune/inflammatory response are strongly dysregulated in AE and other complex disorders. The study confirmed that the susceptibility to AE depends on a complex interaction between latitude, geographical localization, and the differential distribution of genetic variants among populations exposed to similar environmental factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/3457898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582825PMC
January 2020

Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report.

Front Neurol 2019 13;10:619. Epub 2019 Jun 13.

Molecular Genetics Laboratory Unione Italiana Lotta Distrofia Muscolare (UILDM), Santa Lucia Foundation, Rome, Italy.

The diagnosis of LGMD2A (calpainopathy) can be challenging due to genetic heterogeneity and to high similarity with other LGMDs or neuromuscular disorders. In this setting, NGS panels are highly recommended to perform differential diagnosis, identify new causative mutations and enable genotype-phenotype correlations. In this manuscript, the case of a patient affected by LGMD2A is reported, for which the application of a defined custom designed NGS panel allowed to confirm the diagnosis of calpainopathy linked with two heterozygous variants in , namely c.550delA and c.1813G>C. The first variant has been extensively described in relation to calpainopathy. The second variant c.1813G>C, instead, is novel and has been predicted to be probably damaging. In addition, NGS analysis on the proband revealed a heterozygous variant (c.550C>T) in the gene, which is associated with dilated cardiomyopathy. The variant is novel and has been predicted to be deleterious by subsequent bioinformatic analysis. Successively, segregation analysis was performed on family members. Interestingly, none of them showed neuromuscular symptoms but the mother was diagnosed with bradycardia and syncopal episodes and showed a positive family history for cardiomyopathy. The segregation analysis reported that the proband inherited the c.1813G>C () from the father who was a healthy carrier. The mother was positive for c.550delA () and c.550C>T (), suggesting thereby a possible genetic explanation for her cardiovascular problems. Segregation analysis, therefore, confirmed the inheritance pattern of the variants carried by the proband and highlighted a familiarity for cardiomyopathy which should not be neglected. The NGS analysis was further performed on the partner of the proband, to estimate the reproductive risk of the couple. The partner was negative to NGS screening, suggesting thereby a low risk to have an affected child with calpainopathy and 50% probability to inherit the variant. This case report showed the clinical utility of the NGS panel in providing accurate LGMD2A diagnosis and identifying complex phenotypes originating from mutations in multiple genes. However, NGS results should always be accomplished by a dedicated genetic counseling, not only to evaluate the recurrence and reproductive risks but also to uncover unexpected findings which can be clinically significant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585112PMC
June 2019

Laryngopharyngeal Reflux Diagnosis in Obstructive Sleep Apnea Patients Using the Pepsin Salivary Test.

Int J Environ Res Public Health 2019 06 10;16(11). Epub 2019 Jun 10.

Department of 'Organi di Senso', University "Sapienza", Viale dell'Università 33, 00161 Rome, Italy.

Background: To investigate the presence of laryngopharyngeal reflux in patients with obstructive sleep apnea (OSA) employing the salivary pepsin concentration method. To compare the results of pepsin concentration with the severity of the pathology.

Methods: Seventy-five OSA patients (44 males, 31 females) were enrolled in the study. For each patient, the AHI (apnea-hypopnea index) and the BMI (body mass index) were initially evaluated. All the patients enrolled were assessed using the reflux symptom index (RSI) and the reflux finding score (RFS) in order to perform a clinical diagnosis of laryngopharyngeal reflux. In all patients a salivary sample was taken to estimate the presence of pepsin and its concentration.

Results: The incidence of LPR (laryngopharyngeal reflux) in OSA patients, evaluated using the salivary pepsin concentration test (PEP-test), was found to be 32% of cases. Linear regression testing did not show any correlation between AHI and pepsin concentration in salivary samples ( = 0.1).

Conclusion: A high number of patients with OSA seem to show positivity for salivary pepsin, correlated to an LPR. There does not appear to be a correlation between the severity of apnea and the grade of salivary pepsin reflux. On the other hand, direct correlation between BMI and the value of pepsin in salivary specimens was observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph16112056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604010PMC
June 2019

The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of and .

Int J Mol Sci 2019 Mar 29;20(7). Epub 2019 Mar 29.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, 00142 Rome, Italy.

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of , , , , , , , and were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (, G/A) and rs2910164 (, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20071578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480223PMC
March 2019

Facioscapulohumeral muscular dystrophy (FSHD) molecular diagnosis: from traditional technology to the NGS era.

Neurogenetics 2019 05 25;20(2):57-64. Epub 2019 Mar 25.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, via Ardeatina 354, 00142, Rome, Italy.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic neuromuscular disorder which mainly affects the muscles of the face, shoulder, and upper arms. FSHD is generally associated with the contraction of D4Z4 macrosatellite repeats on 4q35 chromosome or mutations in SMCHD1, which are responsible of the toxic expression of DUX4 in muscle tissue. Despite the recent application of NGS techniques in the clinical practice, the molecular diagnosis of FSHD is still performed with dated techniques such as Southern blotting. The diagnosis of FSHD requires therefore specific skills on both modern and less modern analytical protocols. Considering that clinical and molecular diagnosis of FSHD is challenging, it is not surprising that only few laboratories offer a comprehensive characterization of FSHD, which requires the education of professionals on traditional techniques even in the era of NGS. In conclusion, the study of FSHD provides an excellent example of using classical and modern molecular technologies which are equally necessary for the analysis of DNA repetitive traits associated with specific disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-019-00575-4DOI Listing
May 2019

Doyne honeycomb retinal dystrophy - functional improvement following subthreshold nanopulse laser treatment: a case report.

J Med Case Rep 2019 Jan 10;13(1). Epub 2019 Jan 10.

UCL Institute of Ophthalmology, University College, London, UK.

Background: Based on phenotypic similarities between age-related macular degeneration and the autosomal disorder Doyne honeycomb retinal dystrophy, we report on a single nanolaser treatment of a patient with genotype Doyne honeycomb retinal dystrophy confirmation and evidence of disease progression over 12 months. The case study is the first report of short-term results of subthreshold nanolaser treatment in a patient with Doyne honeycomb retinal dystrophy.

Case Presentation: A 43-year-old Caucasian man with moderate loss of visual acuity in his left eye (20/40) and normal visual acuity in his right eye (20/20), with clinical Doyne honeycomb retinal dystrophy diagnosis and genetic confirmation of the common heterozygous mutation (EFEMP1) by genetic testing, underwent nanopulse subthreshold laser treatment in his left eye. A safety examination, carried out 7 days after treatment, and clinical follow-up, conducted 60 days following laser treatment, showed improvement of visual acuity from baseline by two letters and a subjective improvement of blurring. While no apparent morphological changes were found on fundoscopy, increased autofluorescence in the treated eye was observed on imaging. In addition, 2 months after nanopulse subthreshold laser treatment, rod-mediated and cone-mediated full-field electroretinography b-wave amplitudes showed an increase from baseline in both the treated eye (300%) and untreated eye (50%). At 2 months after nanopulse subthreshold laser treatment, multifocal electroretinograms showed improvement. Acuity and full-field electroretinography improvement persisted at 6-month follow-up.

Conclusions: Sustained improvements in retinal function on electroretinography persisted in both eyes 6 months after treatment, suggesting an enhancement of phototransduction and retinoid recycling induced by nanopulse subthreshold laser treatment. The functional improvement observed in the untreated eye is hypothesized to arise from an increased expression and release of metalloproteinases that circulate systemically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-018-1935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327555PMC
January 2019

Expression and potential role of cellular retinol binding protein I in psoriasis.

Oncotarget 2018 Dec 4;9(95):36736-36749. Epub 2018 Dec 4.

Anatomic Pathology Unit, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.

Psoriasis is a diffuse chronic skin disorder characterized from accelerated epidermal turnover and inflammatory cell infiltrate. Retinoids influence keratinocyte proliferation and differentiation as well as inflammatory response. Cellular retinol binding protein (CRBPI) regulates intracellular vitamin A bioavailability and contributes to maintain skin homeostasis. The aim of present study was to investigate the expression of CRBPI and its role in the pathogenesis of skin psoriasis. Immunohistochemistry revealed more diffuse and increased CRBPI expression in all epidermal layers of human psoriatic lesions except in the stratum corneum. An imiquimod-induced psoriatic-like model documented the increase of skin lesional area and severity index score as well as of the severity of microscopic features as parakeratosis, papillomatosis and spongiosis in CRBPI-knockout compared to wild-type mice, associated to the increased keratinocyte CK17 and Ki-67 expression and the reduction of CK1, CRABPII and RXRα. Gene array of imiquimod-induced psoriatic skin documented the greater up-regulation of EGF/PDGF-related genes and down-regulation of EGR1 and pro-inflammatory IL-related genes in CRBPI-knockout compared to wild-type mice. Finally, CRBPI transfection in HaCaT cells increased AKT and NF-κB-related genes and proteins and down-regulated IL-2, IL-6 and IL-8 pro-inflammatory signalling. Although not recognized as a psoriatic susceptibility gene in our cohort of patients, the present data strongly supported the potential role of CRBPI to sustain keratinocyte proliferation and differentiation and to counteract pro-inflammatory genes expression in psoriatic lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298411PMC
December 2018

Digenic Inheritance of Shortened Repeat Units of the D4Z4 Region and a Loss-of-Function Variant in in a Family With FSHD.

Front Neurol 2018 28;9:1027. Epub 2018 Nov 28.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome, Italy.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder which is typically transmitted by an autosomal dominant pattern, although reduced penetrance and sporadic cases caused by mutations, are often observed. FSHD may be caused by a contraction of a repetitive element, located on chromosome 4 (4q35). This locus is named and consists of 11 to more than 100 repeated units (RU). The is normally hypermethylated and the genes located on this locus are silenced. In case of FSHD, the region is characterized by 1-10 repeats and results in the region being hypomethylated. However, 5% of FSHD cases do not carry the short allele of region. To date, two forms of FSHD (FSHD1 and FSHD2) are known. FSHD2 is usually observed in patients without the fragment contraction and carrying variants in (18p11.32) gene. We report the case of a young adult patient who shows severe symptoms of FSHD. Preliminary genetic analysis did not clarify the phenotype, therefore we decided to study the family members by genetic and epigenetic approaches. The analysis of fragment resulted to be 8 RU in the affected proband and in his father; 26 RU in the mother and 25 RU in the maternal uncle. analysis revealed a heterozygous variation within the exon 41. The variant was detected in the proband, her mother and the uncle. Furthermore, epigenetic analysis of CpG6 methylation regions showed significant hypomethylation in the affected patient (54%) and in the mother (56%), in contrast to the father (88%) and the uncle (81%) carrying higher methylation levels. The analysis of DR1 methylation levels reported hypomethylation for the proband (19%), the mother (11%), and the uncle (16%). The father showed normal DR1 methylation levels (>30%). Given these results, the combined inheritance of variant and the short fragment might explain the severe FSHD phenotype displayed by the proband. On this subject, analysis should be promoted in a larger number of patients, even in presence of contractions, to facilitate the genotype-phenotype correlation as well as, to enable a more precise diagnosis and prognosis of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.01027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279899PMC
November 2018

Identification of Duchenne/Becker muscular dystrophy mosaic carriers through a combined DNA/RNA analysis.

Prenat Diagn 2018 12 20;38(13):1096-1102. Epub 2018 Nov 20.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, IRCCS, Rome, Italy.

Objective: The Duchenne/Becker muscular dystrophy (DMD) carrier screening includes the evaluation of mutations in DMD gene, and the most widely used analysis is the multiplex ligation-dependent probe amplification (MLPA) for the DMD deletions/duplications detection. The high frequency of de novo mutations permits to estimate a risk up to 20% of mosaicisms for mothers of sporadic DMD children. The purpose of this study is to evaluate alternative analytical strategy for the detection of mosaics carrier women, in order to improve the recurrence risk estimation.

Method: Different DNA and RNA analyses were conducted on samples from a woman that conceived a DMD fetus without previous family history of dystrophynopathy.

Results: Standard MLPA analysis failed to identify mosaicism, even if MLPA doses suggested it. Electrophoresis and direct sequencing conducted on RNA permitted to detect two different amplicons of cDNAs, demonstrating the presence of somatic mosaicism. Subsequent detection of a second affected fetus confirmed the mosaic status on the mother.

Conclusion: The implementation of RNA analysis in diagnostic algorithm can increase the sensitivity of carrier test for mothers of sporadic affected patients, permitting detection of mosaic status. A revision of analytical guidelines is needed in order to improve the recurrence risk estimation and support prenatal genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5369DOI Listing
December 2018

Application of Precision Medicine in Neurodegenerative Diseases.

Front Neurol 2018 23;9:701. Epub 2018 Aug 23.

Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.

One of the main challenges for healthcare systems is the increasing prevalence of neurodegenerative pathologies together with the rapidly aging populations. The enormous progresses made in the field of biomedical research and informatics have been crucial for improving the knowledge of how genes, epigenetic modifications, aging, nutrition, drugs and microbiome impact health and disease. In fact, the availability of high technology and computational facilities for large-scale analysis enabled a deeper investigation of neurodegenerative disorders, providing a more comprehensive overview of disease and encouraging the development of a precision medicine approach for these pathologies. On this subject, the creation of collaborative networks among medical centers, research institutes and highly qualified specialists can be decisive for moving the precision medicine from the bench to the bedside. To this purpose, the present review has been thought to discuss the main components which may be part of precise and personalized treatment programs applied to neurodegenerative disorders. Parkinson Disease will be taken as an example to understand how precision medicine approach can be clinically useful and provide substantial benefit to patients. In this perspective, the realization of web-based networks can be decisive for the implementation of precision medicine strategies across different specialized centers as well as for supporting clinical/therapeutical decisions and promoting a more preventive and participative medicine for neurodegenerative disorders. These collaborative networks are essentially addressed to find innovative, sustainable and effective strategies able to provide optimal and safer therapies, discriminate at risk individuals, identify patients at preclinical or early stage of disease, set-up individualized and preventative strategies for improving prognosis and patient's quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115491PMC
August 2018

Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants.

Oncotarget 2018 Jan 12;9(8):7812-7821. Epub 2017 Dec 12.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome, Italy.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants ( and ) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.23241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814260PMC
January 2018

and are disease-specific biomarkers for psoriatic arthritis susceptibility.

Oncotarget 2017 Nov 8;8(56):95401-95411. Epub 2017 Sep 8.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome, Italy.

To date, the genes associated with Psoriatic Arthritis (PsA) are principally involved in inflammation, immune response and epidermal differentiation, without any information about the relationship between disease and bone metabolism genes. Our work was focused on 5q31 locus, which contains several genetic variants significantly associated with PsA. The study involved 1526 subjects (500 PsA, 426 PsV, 600 controls). The region was evaluated by selecting and genotyping the SNPs of interest by Real Time PCR and direct sequencing. The results were subjected to biostatistic and bioinformatic analysis. The case-control study highlighted a significant association between and PsA, but not with PsV (Psoriasis Vulgaris) patients. In addition, the haplotype analysis revealed two haplotypes significantly associated with PsA susceptibility. The Linkage Disequilibrium (LD) study showed the presence of a specific block in high LD within 132,692,628-132,737,638 bp of 5q31, giving additional evidence of specific association of the 5q31 region in PsA patients. Moreover, KIF3A expression was assessed by immunohistochemistry assays which showed a marked and significant difference of KIF3A expression between pathological and normal tissues. Our analysis described and as novel susceptibility genes for PsA, suggesting a clear implication of bone metabolism genes in the disease etiopathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.20727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707030PMC
November 2017

Towards the application of precision medicine in Age-Related Macular Degeneration.

Prog Retin Eye Res 2018 03 29;63:132-146. Epub 2017 Nov 29.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Via Ardeatina 354, 00142, Rome, Italy; Department of Biomedicine and Prevention, ''Tor Vergata'' University, Via Montpellier 1, 00133, Rome, Italy. Electronic address:

The review essentially describes genetic and non-genetic variables contributing to the onset and progression of exudative Age-related Macular Degeneration (AMD) in Italian population. In particular, AMD susceptibility within Italian population is contributed to by genetic variants, accounting for 23% of disease and non-genetic variants, accounting for 10% of AMD. Our data highlighted prominent differences concerning genetic and non-genetic contributors to AMD in our cohort with respect to worldwide populations. Among genetic variables, SNPs of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1 were significantly associated with the risk of AMD in the Italian cohort. Surprisingly, other susceptibility variants described in European, American and Asiatic populations, did not reach the significance threshold in our cohort. As expected, advanced age, smoking and dietary habits were associated with the disease. In addition, we also describe a number of gene-gene and gene-phenotype interactions. In fact, AMD-associated genes may be involved in the alteration of Bruch's membrane and induction of angiogenesis, contributing to exacerbate the damage caused by aging and environmental factors. Our review provides an overview of genetic and non-genetic factors characterizing AMD susceptibility in Italian population, outlining the differences with respect to the worldwide populations. Altogether, these data reflect historical, geographic, demographic and lifestyle peculiarities of Italian population. The role of epigenetics, pharmacogenetics, comorbities and genetic counseling in the management of AMD patients have been described, in the perspective of the application of a "population-specific precision medicine" approach addressed to prevent AMD onset and improve patients' quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.preteyeres.2017.11.004DOI Listing
March 2018

Biomolecular index of therapeutic efficacy in psoriasis treated with anti-TNF-α agents.

G Ital Dermatol Venereol 2018 Jun 14;153(3):316-325. Epub 2016 Sep 14.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome Italy.

Background: Clinical or quality of life assessments are currently available for psoriasis severity evaluation and therapeutic response. Laboratory scores focused to measure and follow treatment efficacy are lacking at present.

Methods: A microscopic and biomolecular score was designed to monitor skin disease severity and clinical response to anti-psoriatic treatments. A susceptibility gene analysis on cellular retinoic acid binding protein-II (CRABP-II), acting on keratinocyte differentiation, was also performed. A Molecular Index of Therapeutic Efficacy (MITE) was defined by assembling morphometric/semiquantitative measurement of epidermal thickness, immunohistochemical Ki-67, keratin 17 and CRABP-II expression of lesional and non-lesional psoriatic skin biopsies before and after anti-tumor necrosis factor (TNF) α therapies. A 0-12 MITE score was correlated with Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI) scores and inflammation. Three CRABP-II SNPs were analyzed by TaqMan assay.

Results: All parameters were highly expressed in psoriatic lesions and reduced after 12 weeks of anti-TNF-α treatments. MITE score strongly correlated with PASI and PDI values either before or after therapies (P<0.001 and P<0.001, respectively). Conversely, MITE values did not change after treatments of non-responder patients. CRABP-II did not result in a psoriatic susceptibility gene for the SNPs probes analyzed.

Conclusions: MITE score variations corresponded to the patients' clinical improvement following anti-TNF-α treatments, with significant statistical correlation among MITE, PASI and PDI scores. If confirmed in a larger series and/or in different hyperproliferative and inflammatory dermatoses, MITE score could be proposed as additional monitoring system to evaluate treatment protocols in skin disorders and targeted biomolecular pathways supporting clinical efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0392-0488.16.05427-4DOI Listing
June 2018

Pharmacogenomics of multifactorial diseases: a focus on psoriatic arthritis.

Pharmacogenomics 2016 06 7;17(8):943-51. Epub 2016 Jun 7.

Department of Biomedicine & Prevention, School of Medicine, University of Rome "Tor Vergata", via Montpellier 1, 00133 Rome, Italy.

This review will outline the current pharmacogenomics knowledge about psoriatic arthritis with a special attention to the perspectives and the challenges for its implementation in the clinical practice. To date, different drugs have been developed to contrast the symptoms and the progression of psoriatic arthritis. However, patients have shown high variability of drug response in relation to their genetic makeup. In this context, the advances made in the knowledge and the potentialities of genome-drugs associations paved the path for the development of a precision medicine. In fact, these associations may be successfully combined with the environment information to provide new strategies able to prevent and improve the disease management as well as to enhance the patients quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs.16.20DOI Listing
June 2016