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Maria Luisa SIMONE
Personale tecnico amministrativo
Dipartimento di Scienze della Vita sede ex-Scienze Biomediche
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Pubblicazioni
2022
- Comparison of two polygenic risk score to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects
[Articolo su rivista]
Cefalù, Angelo B.; Spina, Rossella; Noto, Davide; Rabacchi, Claudio; Giammanco, Antonina; Simone, Maria Luisa; Brucato, Federica; Scrimali, Chiara; Gueli-Alletti, Maria Grazia; Barbagallo, Carlo M.; Tarugi, Patrizia; Averna, Maurizio R.
abstract
Background
Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in a given population. Mutations in the candidate genes account only for a small proportion of subjects with HBL suggesting a role for a polygenic contribution to the low cholesterol phenotype.
Objective
To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied.
Methods
The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden.
Results
Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p<0.002) with no differences in the percentage of fatty liver.
Conclusion
Only PRS1 is effective in detecting polygenic HBL while PRS2 does not improve the polygenic diagnosis.
2016
- DIAGNOSI MOLECOLARE DELLE IPERTRIGLICERIDEMIE PRIMITIVE ATTRAVERSO “NGS” (NEXT GENERATION SEQUENCING)
[Abstract in Atti di Convegno]
Rabacchi, Claudio; Tenedini, Elena; Bernardis, Isabella; Simone, Maria Luisa; Tagliafico, Enrico; Tarugi, Patrizia Maria
abstract
L’ipertrigliceridemia severa è
una condizione caratterizzata
da elevati livelli di trigliceridi
(TG) superiori a 1000 mg/dl
ed accumulo di chilomicroni a
digiuno. Questa condizione è
rivelata dalla presenza di
plasma lattescente e può essere
secondaria (es. in corso di
diabete scompensato,
sindrome nefrosica grave etc.)
o primitiva su base genetica. La
forma primitiva prende il
nome di Chilomicronemia
Familiare (CF).
Il quadro clinico della CF può
comprendere: coliche
addominali, pancreatiti
ricorrenti, xantomi eruttivi,
lipemia retinalis, ed
epatomegalia. Questo
disordine ha una modalità di
trasmissione autosomica
recessiva ed è dovuto a
mutazioni in uno dei geni
coinvolti nella cascata lipolitica
intravascolare, il processo
attraverso il quale i trigliceridi
trasportati dai chilomicroni e
dalle VLDL sono idrolizzati nel
plasma.
I principali geni candidati
tradizionalmente considerati
sono cinque: il gene LPL che
codifica per l’enzima lipasi
lipoproteica; il gene APOC2
ed il gene APOA5 che
codificano per due
apolipoproteine che svolgono il
ruolo di attivatori della LPL; il
gene GPIHBP1 che codifica la
piattaforma molecolare per la
LPL, ed infine il gene LMF1
che codifica per una proteina
coinvolta nella maturazione
intracellulare della LPL
2016
- Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing
[Articolo su rivista]
Bernardis, Isabella; Chiesi, Laura; Tenedini, Elena; Artuso, Lucia; Percesepe, Antonio; Artusi, Valentina; Simone, Maria Luisa; Manfredini, Rossella; Camparini, Monica; Rinaldi, Chiara; Ciardella, Antonio; Graziano, Claudio; Balducci, Nicole; Tranchina, Antonia; Cavallini, Gian Maria; Pietrangelo, Antonello; Marigo, Valeria; Tagliafico, Enrico
abstract
To assess the clinical utility of targeted Next-Generation Sequencing (NGS) for the diagnosis of Inherited Retinal Dystrophies (IRDs), a total of 109 subjects were enrolled in the study, including 88 IRD affected probands and 21 healthy relatives. Clinical diagnoses included Retinitis Pigmentosa (RP), Leber Congenital Amaurosis (LCA), Stargardt Disease (STGD), Best Macular Dystrophy (BMD), Usher Syndrome (USH), and other IRDs with undefined clinical diagnosis. Participants underwent a complete ophthalmologic examination followed by genetic counseling. A custom AmpliSeq� panel of 72 IRD-related genes was designed for the analysis and tested using Ion semiconductor Next-Generation Sequencing (NGS). Potential disease-causing mutations were identified in 59.1% of probands, comprising mutations in 16 genes. The highest diagnostic yields were achieved for BMD, LCA, USH, and STGD patients, whereas RP confirmed its high genetic heterogeneity. Causative mutations were identified in 17.6% of probands with undefined diagnosis. Revision of the initial diagnosis was performed for 9.6% of genetically diagnosed patients. This study demonstrates that NGS represents a comprehensive cost-effective approach for IRDs molecular diagnosis. The identification of the genetic alterations underlying the phenotype enabled the clinicians to achieve a more accurate diagnosis. The results emphasize the importance of molecular diagnosis coupled with clinic information to unravel the extensive phenotypic heterogeneity of these diseases.
2015
- Implementation of an NGS-based workflow for BRCA1 and BRCA2 mutation screening
[Abstract in Atti di Convegno]
Artuso, Lucia; Medici, Veronica; Bernardis, Isabella; Tenedini, Elena; Artusi, Valentina; Simone, Maria Luisa; Tarugi, Patrizia Maria; Manfredini, Rossella; Cortesi, Laura; Tagliafico, Enrico
abstract
probability to develop familiar breast cancer. To detect BRCA1/2 germline mutations we developed a next-generation sequencing (NGS) routine dia- gnostic workflow, based on the Ion Torrent PGMTM System platform. The Ion AmpliSeqTM BRCA1 and BRCA2 Community Panel was handled with a semi- automatized procedure for multiplex PCR-based library preparation and se- quencing. Data analysis required the implementation of a custom designed bioinformatic pipeline for sequences alignment and for the identification, annotation and filtration of genetic variants. Sanger sequencing was perfor- med to validate candidate mutations, and to re-sequence amplicons having low NGS coverage (<50 reads per amplicon). Negative samples were ana- lyzed using the BRCA HP Kit (Multiplicom) for an effective homopolymeric stretches detection. This workflow together with the potentiality of our bio- informatic pipeline was blindly tested and validated onto a small cohort of patients previously Sanger sequenced, fine-tuning the parameter settings and resulting in a sensitivity of 100% in variant detection. Subsequently, 244 patients were analyzed thus confirming the need of a double check for the homopolymeric stretches with both NGS sequencing and BRCA HP Kit. The NGS-based workflow here proposed was able to decrease the overall
2014
- Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors
[Articolo su rivista]
Pedroni, Monica; DI GREGORIO, Carmela; Cortesi, Laura; REGGIANI BONETTI, Luca; Magnani, Giulia; Simone, Maria Luisa; Medici, Veronica; PRIORE OLIVA, Claudio; Marino, Marco; PONZ DE LEON, Maurizio
abstract
Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.
2009
- A novel deletion of BRCA1 gene that eliminates the ATG initiation codon without affecting the promoter region.
[Articolo su rivista]
Marino, Marco; Rabacchi, Claudio; Simone, Maria Luisa; Medici, Veronica; Cortesi, L; CALANDRA BUONAURA, Sebastiano
abstract
BackgroundPoint mutations in the highly penetrant cancer susceptibility gene BRCA1 are responsible for the majority of hereditary breast and/or ovarian cancer. We describe a novel large rearrangement of the BRCA1 gene identified in an Italian woman affected by an early onset bilateral breast cancer and a family history of hereditary breast cancer. The proband and her parents were negative for the presence of point mutations in BRCA1 and BRCA2 genes.MethodsMultiplex ligation-dependent probe amplification (MLPA) was used to detect rearrangements in the BRCA1 gene. The breakpoint of the rearrangement identified in the proband was defined by restriction mapping and PCR amplification. BRCA1 mRNA encoded by the mutant allele was isolated from peripheral blood.ResultsThe proband was heterozygous for a 9.1 kb deletion spanning from intron 1 to intron 3 (g.1238_10350del) that eliminates exons 2 and 3 in the mature mRNA. In mutant mRNA exon 1a joins directly to exon 5 with no disruption of the reading frame.ConclusionsThis deletion that eliminates the ATG initiation site in exon 2 and the sequence located in exons 2 and 3 encoding part of the RING finger domain of BRCA1 protein, is expected to abolish the function of this protein.
2009
- First human case of Usutu virus neuroinvasive infection, Italy, August-September 2009.
[Articolo su rivista]
M., Pecorari; G., Longo; W., Gennari; Grottola, Antonella; Sabbatini, Anna Maria Teresa; S., Tagliazucchi; G., Savini; F., Monaco; Simone, Maria Luisa; R., Lelli; F., Rumpianesi
abstract
We report the first worldwide case of Usutu virus (USUV) neuroinvasive infection in a patient with diffuse large B cell lymphoma who presented with fever and neurological symptoms and was diagnosed with meningoencephalitits. The cerebrospinal fluid was positive for USUV, and USUV was also demonstrated in serum and plasma samples by RT-PCR and sequencing. Partial sequences of the premembrane and NS5 regions of the viral genome were similar to the USUV Vienna and Budapest isolates.
2006
- A novel compound heterozigous mutation of the aromatase gene in an adult man
[Abstract in Atti di Convegno]
Laura, Maffei; Rochira, Vincenzo; Evan R., Simpson; Simone, Maria Luisa; Claudio, Aranda; Bibiana, Fabre; M., Stivel; Luberto, Alessandra; Antonio, Balestrieri; Pignatti, Elisa; Paula, Antunez; Carani, Cesare
abstract
Descriptions of a new case of human aromatase deficiency useful for a better understanding of male oestrogen pathophysiology
2006
- A novel compound heterozigous mutation of the aromatase gene in an adult manl
[Abstract in Atti di Convegno]
Laura, Maffei; Rochira, Vincenzo; Evan R., Simpson; Simone, Maria Luisa; Claudio, Aranda; Bibiana, Fabre; Mirta, Stivel; Luberto, Alessandra; Antonio, Balestrieri; Pignatti, Elisa; Paula, Antunez; Carani, Cesare
abstract
Descriptions of a new case of human aromatase deficiency useful for a better understanding of male oestrogen pathophysiology