Publications by authors named "Antonio Pizzuti"

121 Publications

Risk of neural tube defects according to maternal body mass index: a systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2021 Jul 5:1-10. Epub 2021 Jul 5.

Department of Maternal and Child Health and Urologynecological Sciences, Sapienza University of Rome, Umberto I Hospital, Rome, Italy.

Introduction: The aim of our systematic review and meta-analysis was to evaluate the risk of neural tube defects (NTDs) according to the pre-pregnancy body mass index.

Materials And Methods: Electronic databases were searched (MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, and Cochrane Library). Selection criteria included prospective and retrospective cohort studies reporting the prevalence of fetal NTDs in obese, overweight, and underweight pregnant women. Odds ratios (ORs) comparing risk among these subsets of pregnancies with normal weight mothers were determined with 95% confidence intervals (CI). The evaluated outcome was the association between maternal underweight, overweight, and obesity and the risk of NTDs.

Results: We included ten studies published between 2000 and 2017, including underweight, overweight, and obese pregnant women with fetal NTD (cases) and pregnant women with recommended BMI with fetal NTD (controls). Compared with normal BMI women, obese mothers were at significantly higher risk of fetal NTDs (0.53 0.33%; OR 1.62 95% CI 1.32-1.99,  < .0001), while no difference for the risk of NTDs was found when comparing overweight (0.34 0.32%; OR 1.09 95% CI 0.92-1.3,  = .3) and underweight (0.65 0.24%; OR 1.34 95% CI 0.73-2.47,  = .34) with normal weight pregnant women.

Discussion: Obese pregnant women are at significantly higher risk NTDs, while no significant difference has been found in overweight and underweight pregnant women. Key message Obese pregnant women are at significantly higher risk of NTDs, such as spina bifida compared with normal weight women. No difference was found when comparing overweight and underweight with normal weight women.
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http://dx.doi.org/10.1080/14767058.2021.1946789DOI Listing
July 2021

External hydrocephalus as a prenatal feature of noonan syndrome.

Ann Hum Genet 2021 Jun 2. Epub 2021 Jun 2.

Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

Brain malformations have been reported in RASopathies, including postnatal external hydrocephalus, a nonobstructive form of cerebrospinal fluid accumulation around the brain. It was described in a few patients with mutations of other genes than PTPN11, such as SOS1 and SHOC2 and never in prenatal diagnosis. The aim of this case report is to describe the prenatal presentation of a fetus with Noonan syndrome (NS) and external hydrocephalus. We report on a Noonan syndrome fetus with a de novo pathogenic PTPN11 c.923A>G p.Asn308Ser mutation, showing external hydrocephalus, an extremely rare fetal finding, corpus callosum, and cerebellar vermis under the 10th centile, plus a typical NS cardiopathy. This is the first case of Noonan syndrome prenatal diagnosis in a fetus presenting with external hydrocephalus. Following pathophysiological considerations, we suggest to consider NS in the differential diagnosis of external hydrocephalus, investigating other evocative findings and considering molecular screening for mutations in NS-related genes.
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http://dx.doi.org/10.1111/ahg.12436DOI Listing
June 2021

Altered Expression of Candidate Genes in Mayer-Rokitansky-Küster-Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X.

Biology (Basel) 2021 May 21;10(6). Epub 2021 May 21.

Department of Experimental Medicine, Sapienza University of Rome-Viale Regina Elena 324, 00161 Rome, Italy.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare and complex disease defined by congenital aplasia of the vagina and uterus in 46,XX women, often associated with kidney and urinary tract anomalies. The aetiopathogenesis of MRKH syndrome is still largely unknown. Herein, we investigated the role of selected candidate genes in the aetiopathogenesis of MRKH syndrome, with a focus on , which encodes for protein kinase X. Through RT-qPCR analyses performed on vaginal dimple samples from patients, and principal component analysis (PCA), we highlighted a phenotype-related expression pattern of , , and in MRKH patients. By using an in vitro approach, we proved that PRKX ectopic overexpression in a cell model of vaginal keratinocytes promotes cell motility through epithelial-to-mesenchymal transition (EMT) activation, a fundamental process in urogenital tract morphogenesis. Moreover, our findings showed that PRKX upregulation in vaginal keratinocytes is able to affect transcriptional levels of genes, implicated in urinary and genital tract development. Our study identified the dysregulation of PRKX expression as a possible molecular cause for MRKH syndrome. Moreover, we propose the specific role of PRKX in vaginal keratinocyte biology as one of the possible mechanisms underlying this complex disease.
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http://dx.doi.org/10.3390/biology10060450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223793PMC
May 2021

Fetal dacryocystocele: A pitfall in the third-trimester prenatal diagnosis of cleft lip.

J Clin Ultrasound 2021 Sep 27;49(7):777-778. Epub 2021 May 27.

Department of Maternal and Child Health and Urologynecological Sciences, Sapienza University of Rome, Umberto I Hospital, Viale del Policlinico n° 155, Rome, 00161, Italy.

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http://dx.doi.org/10.1002/jcu.23023DOI Listing
September 2021

miR-125b/NRF2/HO-1 axis is involved in protection against oxidative stress of cystic fibrosis: A pilot study.

Exp Ther Med 2021 Jun 2;21(6):585. Epub 2021 Apr 2.

Department of Molecular Medicine, Sapienza University of Rome, I-00161 Rome, Italy.

In the physiopathology of cystic fibrosis (CF), oxidative stress implications are recognized and widely accepted. The cystic fibrosis transmembrane conductance regulator (CFTR) defects disrupt the intracellular redox balance causing CF pathological hallmarks. Therefore, oxidative stress together with aberrant expression levels of detoxification genes and microRNAs (miRNAs/miRs) may be associated with clinical outcome. Using total RNA extracted from epithelial nasal cells, the present study analyzed the expression levels of oxidative stress genes and one miRNA using quantitative PCR in a representative number of patients with CF compared with in healthy individuals. The present pilot study revealed the existence of an association among CFTR, genes involved in the oxidative stress response and miR-125b. The observed downregulation of CFTR gene expression was accompanied by increased expression levels of Nuclear factor erythroid derived-2 like2 and its targets NAD(P)H:Quinone Oxidoreductase and glutathione S-transferase 1. Moreover, the expression levels of heme oxygenase-1 (HO-1) and miR-125b were positively correlated with a forced expiratory volume in 1 sec (FEV1) >60% in patients with CF with chronic lung infection (r=0.74; P<0.001 and r=0.57; P<0.001, respectively). The present study revealed the activation of an inducible, but not fully functional, oxidative stress response to protect airway cells against reactive oxygen species-dependent injury in CF disease. Additionally, the correlations of HO-1 and miR-125b expression with an improved FEV1 value suggested that these factors may synergistically protect the airway cells from oxidative stress damage, inflammation and apoptosis. Furthermore, HO-1 and miR-125b may be used as prognostic markers explaining the wide CF phenotypic variability as an additional control level over the CFTR gene mutations.
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http://dx.doi.org/10.3892/etm.2021.10017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027740PMC
June 2021

OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.

Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC.
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http://dx.doi.org/10.3390/cancers13071519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059141PMC
March 2021

Susceptibility to ischaemic heart disease: Focusing on genetic variants for ATP-sensitive potassium channel beyond traditional risk factors.

Eur J Prev Cardiol 2020 Jun 2. Epub 2020 Jun 2.

Department of Clinical, Internal, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Aims: Ischaemic heart disease is classically associated with coronary artery disease. Recent evidences showed the correlation between coronary microvascular dysfunction and ischaemic heart disease, even independently of coronary artery disease. Ion channels represent the final effectors of blood flow regulation mechanisms and their genetic variants, in particular of Kir6.2 subunit of the ATP-sensitive potassium channel (KATP), are reported to be involved in ischaemic heart disease susceptibility. The aim of the present study is to evaluate the role of KATP channel and its genetic variants in patients with ischaemic heart disease and evaluate whether differences exist between coronary artery disease and coronary microvascular dysfunction.

Methods: A total of 603 consecutive patients with indication for coronary angiography due to suspected myocardial ischaemia were enrolled. Patients were divided into three groups: coronary artery disease (G1), coronary microvascular dysfunction (G2) and normal coronary arteries (G3). Analysis of four single nucleotide polymorphisms (rs5215, rs5216, rs5218 and rs5219) of the KCNJ11 gene encoding for Kir6.2 subunit of the KATP channel was performed.

Results: rs5215 A/A and G/A were significantly more represented in G1, while rs5215 G/G was significantly more represented in G3, rs5216 G/G and C/C were both more represented in G3, rs5218 C/C was more represented in G1 and rs5219 G/A was more represented in G1, while rs5219 G/G was significantly more represented in G2. At multivariate analysis, single nucleotide polymorphism rs5215_G/G seems to represent an ischaemic heart disease independent protective factor.

Conclusions: These results suggest the potential role of KATP genetic variants in ischaemic heart disease susceptibility, as an independent protective factor. They may lead to a future perspective for gene therapy against ischaemic heart disease.
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http://dx.doi.org/10.1177/2047487320926780DOI Listing
June 2020

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort.

Genet Med 2021 06 10;23(6):1116-1124. Epub 2021 Feb 10.

Pediatrics Department, Medical Genetics Division, CHU Sainte-Justine, Montreal, QC, Canada.

Purpose: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype-phenotype correlations.

Methods: Three hundred fifty-two chromosomal microarray-negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons.

Results: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM.

Conclusion: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.
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http://dx.doi.org/10.1038/s41436-020-01093-7DOI Listing
June 2021

Fetal early motor neuron disruption and prenatal molecular diagnosis in a severe BICD2-opathy.

Am J Med Genet A 2021 05 5;185(5):1509-1514. Epub 2021 Feb 5.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

BICD2 (BICD Cargo Adaptor 2, MIM*609797) mutations are associated with severe prenatal-onset forms of spinal muscular atrophy, lower extremity-predominant 2B (SMALED2B MIM 618291) or milder forms with childhood-onset (SMALED2A MIM 615290). Etiopathogenesis is not fully clarified and a wide spectrum of phenotypic presentations is reported, ranging from extreme prenatal forms with adverse outcome, to slow progressive late-onset forms. We report a fetus at 22 gestational weeks with evidence of Arthrogryposis Multiplex Congenita on ultrasound, presenting with fixed extended lower limbs and flexed upper limbs, bilateral clubfoot and absent fetal movements. A trio-based prenatal Exome Sequencing was performed, disclosing a de novo heterozygous pathogenic in frame deletion (NM_015250.3: c.1636_1638delAAT; p.Asn546del) in BICD2. After pregnancy termination, quantitative analysis on NeuN immunostained spinal cord sections of the ventral horns, revealed that neuronal density was markedly reduced compared to the one of an age-matched normal fetus and an age-matched type-I Spinal Muscular Atrophy sample, used as a comparative model. The present case, the first prenatally diagnosed and neuropathologically characterized, showed an early motor neuron loss in SMALED2B, providing further insight into the pathological basis of BICD2-opathies.
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http://dx.doi.org/10.1002/ajmg.a.62111DOI Listing
May 2021

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives-A Systematic Review.

Diagnostics (Basel) 2021 Feb 2;11(2). Epub 2021 Feb 2.

Department of Experimental Medicine, Policlinico Umberto I Hospital, Sapienza University of Rome, 00161 Rome, Italy.

The introduction of Next Generation Sequencing (NGS) technologies has exerted a significant impact on prenatal diagnosis. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained. We performed a systematic literature review to evaluate the diagnostic yield, as well as inconclusive and negative-result rates of pES. Papers were divided in two groups. The former includes fetuses presenting structural anomalies, regardless the involved organ; the latter focuses on specific class anomalies. Available findings on non-informative or negative results were gathered as well. In the first group, the weighted average diagnostic yield resulted 19%, and inconclusive finding rate 12%. In the second group, the percentages were extremely variable due to differences in sample sizes and inclusion criteria, which constitute major determinants of pES efficiency. Diagnostic pES availability and its application have a pivotal role in prenatal diagnosis, though more homogeneity in access criteria and a consensus on clinical management of controversial information management is envisageable to reach widespread use in the near future.
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http://dx.doi.org/10.3390/diagnostics11020224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913004PMC
February 2021

X-linked dominant RPGR gene mutation in a familial Coats angiomatosis.

BMC Ophthalmol 2021 Jan 14;21(1):37. Epub 2021 Jan 14.

Department of Experimental Medicine, Faculty of Medicine and Odontology, Sapienza University of Rome, p. le A. Moro 5, 00185, Rome, Italy.

Background: Retinitis Pigmentosa (RP) is the most frequent retinal hereditary disease and every kind of transmission pattern has been described. The genetic etiology of RP is extremely heterogeneous and in the last few years the large application of Next Generation Sequencing (NGS) approaches improved the diagnostic yield, elucidating previously unexplained RP causes and new genotype-phenotype correlations. The objective of this study was to reevaluate a previously reported family affected by Coats'-type RP without genetic diagnosis and to describe the new genetic findings.

Case Presentation: Cohort, prospective, and single-center observational family case. Three individuals of a family, consisting of a mother and four sons, with a Coats phenotype were revaluated after 25 years of clinical follow-up using visual acuity tests, ophthalmoscopy, Goldmann visual field, electroretinography (ERG), and spectral domain-optical coherence tomography (SD-OCT). Specifically, a RP NGS panel was performed on one member of the family and segregation analysis was required for the other affected and unaffected members. NGS analysis disclosed a RPGR (Retinitis Pigmentosa GTPase Regulator) gene truncating variant segregating with the phenotype in all the three affected members. RPGR mutations are reported as causative of an X-linked RP.

Conclusions: This is the first reported family with a Coats'-type RP associated to a RPGR mutation and segregating as a dominant X-linked disease, confirming the hypothesis of the genetic origin of this condition and expanding the phenotypic spectrum of diseases caused by RPGR gene mutations. The Authors suggest RPGR gene screening mutations in patients presenting this phenotype.
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http://dx.doi.org/10.1186/s12886-020-01791-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807486PMC
January 2021

Protein-protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer-Rokitansky-Küster-Hauser syndrome.

Sci Rep 2021 01 11;11(1):448. Epub 2021 Jan 11.

Department of Experimental Medicine, Sapienza Università Di Roma, Viale del Policlinico, 155, 00161, Rome, Italy.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.
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http://dx.doi.org/10.1038/s41598-020-79827-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801512PMC
January 2021

Identification of a novel RUNX2 gene mutation and early diagnosis of CCD in a cleidocranial dysplasia suspected Iranian family.

Clin Case Rep 2020 Dec 3;8(12):2333-2340. Epub 2020 Apr 3.

Medical Genetics Department DeNA Laboratory Tehran Iran.

This research resulted in the identification and submission of a novel RUNX2 gene mutation in the affected members of the studied pedigree. Mutation screening is an effective method for the early diagnosis of CCD in the affected individuals.
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http://dx.doi.org/10.1002/ccr3.2825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752336PMC
December 2020

GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations.

Bone 2021 03 12;144:115803. Epub 2021 Jan 12.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

Introduction: Brachydactyly is a bone development abnormality presenting with variable phenotypes and different transmission patterns. Mutations in GDF5 (Growth and Differentiation Factor 5, MIM *601146) account for a significant amount of cases. Here, we report on a three-generation family, where the proband and the grandfather have an isolated brachydactyly with features of both type A1 (MIM #112500) and type C (MIM #113100), while the mother shows only subtle hand phenotype signs.

Materials And Methods: Whole Exome Sequencing (WES) was performed on the two affected individuals. An in-depth analysis of GDF5 genotype-phenotype correlations was performed through literature reviewing and retrieving information from several databases to elucidate GDF5-related molecular pathogenic mechanisms.

Results: WES analysis disclosed a pathogenic variant in GDF5 (NM_000557.5:c.157dup; NP_000548.2:p.Leu53Profs*41; rs778834209), segregating with the phenotype. The frameshift variant was previously associated with Brachydactyly type C (MIM #113100), in heterozygosity, and with the severe Grebe type chondrodysplasia (MIM #200700), in homozygosity. In-depth analysis of literature and databases allowed to retrieve GDF5 mutations and correlations to phenotypes. We disclosed the association of 49 GDF5 pathogenic mutations with eight phenotypes, with both autosomal dominant and recessive transmission patterns. Clinical presentations ranged from severe defects of limb morphogenesis to mild redundant ossification. We suggest that such clinical gradient can be linked to a continuum of GDF5-activity variation, with loss of GDF5 activity underlying bone development defects, and gain of function causing disorders with excessive bone formation.

Conclusions: Our analysis of GDF5 pathogenicity mechanisms furtherly supports that mutation and zygosity backgrounds resulting in the same level of GDF5 activity may lead to similar phenotypes. This information can aid in interpreting the potential pathogenic effect of new variants and in supporting an appropriate genetic counseling.
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http://dx.doi.org/10.1016/j.bone.2020.115803DOI Listing
March 2021

Incidental SOS1 variant identified by non-invasive prenatal screening: Prenatal diagnosis and family clinical reassessment.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 10;256:518-520. Epub 2020 Nov 10.

Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

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http://dx.doi.org/10.1016/j.ejogrb.2020.11.003DOI Listing
January 2021

Recurrent prenatal PIEZO1-related lymphatic dysplasia: Expanding molecular and ultrasound findings.

Eur J Med Genet 2021 Jan 20;64(1):104106. Epub 2020 Nov 20.

Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

Generalized lymphatic dysplasia (GLD), characterized by lymphedema, lymphangiectasias, chylothorax, effusions, represents a recognized cause of fetal hydrops. We describe for the first time recurrent pregnancies showing different ultrasound presentations of lymphatic dysplasia. The first fetus displayed diffuse subcutaneous cysts and septations while the second one presented fetal hydrops. Exome sequencing results at 18 gestational weeks in the second pregnancy showed compound heterozygosity for two novel PIEZO1 variants, afterwards detected also in the first fetus and in the heterozygous parents. Both ultrasound and genetic findings expand the current knowledge of PIEZO1-related GLD. We suggest exome sequencing in hydropic fetuses with normal cytogenetics and in pregnancies with recurrent hydrops/lymphatic dysplasia.
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http://dx.doi.org/10.1016/j.ejmg.2020.104106DOI Listing
January 2021

Pregnant women's knowledge and behaviour to prevent cytomegalovirus infection: an observational study.

J Perinat Med 2021 Mar 23;49(3):327-332. Epub 2020 Oct 23.

Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, Sapienza University of Rome, Rome, Italy.

Objectives: Congenital cytomegalovirus (cCMV) infection can negatively affect pregnancy outcomes, but may be prevented by simple precautions. Literature suggests that gynaecologists do not always adequately inform about preventive behaviour and most pregnant women have a low-level knowledge regarding cCMV infection. The aim of this study is to evaluate knowledge and risk behaviours related to cCMV infection in an unselected group of pregnant women.

Methods: An institutional based cross-sectional study was conducted in three Maternal and Fetal Divisions in Rome between November and February 2019 on 296 pregnant women, their knowledge on cCMV was measured using six cytomegalovirus (CMV) related questions.

Results: Out of the 296 respondents, 59.1% had heard, read or seen information about cCMV infection. Regarding the way of transmission, 96/296 (32.4%) correctly recognize children as a potential source of the infection but only 25/296 (8.44%) knew all prevention practices, 28/296 (9.5%) of women reported that they have never performed cCMV test during pregnancy.

Conclusions: The results of this survey show that knowledge on cCMV infection among pregnant women is poor. This highlights the need to improve counselling on all preventive practices for cCMV infection during perinatal care consultation.
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http://dx.doi.org/10.1515/jpm-2020-0301DOI Listing
March 2021

Obstetrical and perinatal outcomes in fetuses with early versus late sonographic diagnosis of short femur length: A single-center, prospective, cohort study.

Eur J Obstet Gynecol Reprod Biol 2020 Nov 17;254:170-174. Epub 2020 Sep 17.

Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Italy.

Objectives: The aim of this study was to evaluate obstetrical and perinatal outcomes in fetuses with short femur length diagnosed before or after 24 weeks of gestation.

Study Design: This was a prospective cohort study on singleton pregnancies with a diagnosis of fetal femur < 5 centile. Included patients were divided into two groups: patients with a first diagnosis of femur length < 5th percentile at 14-24 weeks (group A) and those with the first diagnosis made at > 24 weeks (group B).

Results: 147 patients were included for the analysis. Group A and group B included 66 (44.9%) and 81 (55.1%) cases. Abnormal fetal karyotype and skeletal dysplasia rates were significantly higher (27.3% vs 3.7%,P < 0.001 and 19.7% vs 3.7%, P = 0.002) in group A. Women in group B had a higher incidence of small for gestational age and intrauterine growth restriction (7.6% vs 24.7%, P = 0.007 and 19.7% vs 44.4%, P = 0.002). There was a significant higher incidence of live births in group B (34.9% vs 97.5%, P < 0.001), while the rate of termination of pregnancy was increased in group A (56.1% vs 1.2%, P < 0.001). No significant difference was found in perinatal outcomes of live births, when comparing group A and B.

Conclusions: The incidence of abnormal karyotype and skeletal dysplasia is higher when short femur length diagnosed earlier in gestation, while the incidence of small for gestational age, intrauterine growth restriction and the rate of live births are significantly increased when short femur length is diagnosed later during pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2020.09.026DOI Listing
November 2020

Beyond and : Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers.

J Clin Med 2020 Sep 17;9(9). Epub 2020 Sep 17.

Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, 00100 Rome, Italy.

The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes and explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than and to correlate the genotype with the clinical phenotype. A cohort of 113 non- patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the gene, and a new pathogenic variant was detected in the gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.
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http://dx.doi.org/10.3390/jcm9093003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563793PMC
September 2020

An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene.

Clin Case Rep 2020 Aug 2;8(8):1445-1451. Epub 2020 Jun 2.

Department of Biomedicine and Prevention University of Rome "Tor Vergata'' Italy.

We characterize a large Italian family presenting with Marfan syndrome (MFS), where the same NM_000138.4:c.6872-1G > T splice site mutation in the FBN1 gene was detected in 37 affected individuals with different pathological phenotypes. Further studies on such a large pedigree could identify other genetic factors that influence MFS manifestation.
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http://dx.doi.org/10.1002/ccr3.2881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455403PMC
August 2020

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in in a Large Cohort of Italian Patients.

Front Neurol 2020 29;11:646. Epub 2020 Jul 29.

Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM ( < 0.01) and in Hyper/NormoPP than in HypoPP2 ( = 0.02). Cold-induced myotonia was more frequently observed in PMC ( = 34) than in SCM ( = 23) ( = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP ( = 4), SCM ( = 5), and PMC ( = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC ( < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
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http://dx.doi.org/10.3389/fneur.2020.00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403394PMC
July 2020

Role of ductus venosus agenesis in right ventricle development.

J Matern Fetal Neonatal Med 2020 Aug 25:1-4. Epub 2020 Aug 25.

Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

Ductus venosus agenesis (DVA) results from portal-umbilical and hepatic-systemic venous system connection failure. Despite a large series of DVA was reported, an accurate description of single fetus cardiac trend with hemodynamic consequences is missing. We describe two fetuses with DVA early detection, comparing right ventricle (RV) development in extrahepatic and intrahepatic drainages. In extrahepatic drainage, the RV was larger and slightly hypertrophic. In intrahepatic drainage, the RV showed reduced dimensions. Ventricle dimension differences decreased and became balanced in perinatal period. Detection of non-balanced ventricles in early second trimester should lead to sonographic follow-up. If DVA is hypothesized, it is important to identify other subdiaphragmatic connections that could alter cardiac preload and ventricle development.
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http://dx.doi.org/10.1080/14767058.2020.1810231DOI Listing
August 2020

An observational study to assess Italian obstetrics providers' knowledge about preventive practices and diagnosis of congenital cytomegalovirus.

J Perinat Med 2020 Aug 25;49(1):67-72. Epub 2020 Aug 25.

Department of Maternal and Child Health and Urological Sciences, "Sapienza" University of Rome, Policlinico Umberto I Hospital, Rome, Italy.

Objectives: Congenital cytomegalovirus (cCMV) infection can be easily prevented by hygienic measures. Up to date the majority of the studies in literature highlighted a reduction in cCMV antenatal counseling and its prevention. Our purpose was to evaluate obstetrics providers' knowledge about cCMV infection, management and the behavioral practices to avoid it.

Methods: This is a cross-sectional survey carried out in Umberto I Hospital, "Sapienza" University of Rome between November 2019 and January 2020. We recruited 148 specialists and residents in Obstetrics and Gynecology through online anonymous multiple-choice 13-questions, 10 min-survey comparing responses between the two groups.

Results: A total of 94.6% of all participants said they always prescribe cytomegalovirus (CMV) serum screening: 73.6% of them regularly counsel about preventive practices, with specialists recording higher percentages (85.4 vs. 65.1%, p<0.005). We identified a good knowledge about the diagnostic pathway, but only 58.1% of our population knows the correct time of late amniocentesis. 12.2% of providers do not consider magnetic resonance (MRI) as a complementary exam.

Conclusions: Prevention of maternal seroconversion is crucial: even if our data show an acceptable knowledge about antenatal counseling, we encourage clinicians to firmly inform and educate women about behavioral measures.
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http://dx.doi.org/10.1515/jpm-2020-0224DOI Listing
August 2020

12q21 deletion syndrome: Narrowing the critical region down to 1.6 Mb including SYT1 and PPP1R12A.

Am J Med Genet A 2020 09 6;182(9):2133-2138. Epub 2020 Jul 6.

Department of Medical Genetics, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.

Deletions in the 12q21 region are rare and non-recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2-3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short-upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A.
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http://dx.doi.org/10.1002/ajmg.a.61734DOI Listing
September 2020

Neonatal Marfan Syndrome by Inherited Mutation.

Indian J Pediatr 2021 02 17;88(2):176-177. Epub 2020 Jun 17.

Department of Pediatrics, Obstetrics and Gynecology, Policlinico Umberto I Hospital, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy.

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http://dx.doi.org/10.1007/s12098-020-03411-yDOI Listing
February 2021

Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co-inheritance.

Mol Genet Genomic Med 2020 08 10;8(8):e1336. Epub 2020 Jun 10.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Background: Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease-causing.

Methods: A trio-based clinical exome sequencing (CES) was performed.

Results: Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM_139058.3:c.922G>T; NP_620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild-type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents.

Conclusion: This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS.
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http://dx.doi.org/10.1002/mgg3.1336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434725PMC
August 2020

Susceptibility to ischaemic heart disease: Focusing on genetic variants for ATP-sensitive potassium channel beyond traditional risk factors.

Eur J Prev Cardiol 2020 Jun 2:2047487320926780. Epub 2020 Jun 2.

Department of Clinical, Internal, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Aims: Ischaemic heart disease is classically associated with coronary artery disease. Recent evidences showed the correlation between coronary microvascular dysfunction and ischaemic heart disease, even independently of coronary artery disease. Ion channels represent the final effectors of blood flow regulation mechanisms and their genetic variants, in particular of Kir6.2 subunit of the ATP-sensitive potassium channel (K), are reported to be involved in ischaemic heart disease susceptibility. The aim of the present study is to evaluate the role of K channel and its genetic variants in patients with ischaemic heart disease and evaluate whether differences exist between coronary artery disease and coronary microvascular dysfunction.

Methods: A total of 603 consecutive patients with indication for coronary angiography due to suspected myocardial ischaemia were enrolled. Patients were divided into three groups: coronary artery disease (G1), coronary microvascular dysfunction (G2) and normal coronary arteries (G3). Analysis of four single nucleotide polymorphisms (rs5215, rs5216, rs5218 and rs5219) of the gene encoding for Kir6.2 subunit of the K channel was performed.

Results: rs5215 A/A and G/A were significantly more represented in G1, while rs5215 G/G was significantly more represented in G3, rs5216 G/G and C/C were both more represented in G3, rs5218 C/C was more represented in G1 and rs5219 G/A was more represented in G1, while rs5219 G/G was significantly more represented in G2. At multivariate analysis, single nucleotide polymorphism rs5215_G/G seems to represent an ischaemic heart disease independent protective factor.

Conclusions: These results suggest the potential role of K genetic variants in ischaemic heart disease susceptibility, as an independent protective factor. They may lead to a future perspective for gene therapy against ischaemic heart disease.
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http://dx.doi.org/10.1177/2047487320926780DOI Listing
June 2020

T399I Polymorphism and Endometriosis in a Cohort of Italian Women.

Diagnostics (Basel) 2020 Apr 27;10(5). Epub 2020 Apr 27.

Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, 00161 Rome, Italy.

Background: Endometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis.

Methods: The gene T399I SNP (C/T transition, rs4986791) was investigated in 236 Italian endometriosis patients and 150 controls by using the PCR-RFLP method. One-tailed Fisher's exact test was used to compare differences between categorical variables. T399I genotype distribution was evaluated for Hardy-Weinberg equilibrium in both groups using the Chi-squared test for given probabilities.

Results: Fisher's exact test comparing C and T allele frequencies showed a difference in the frequency of T alleles between patients and controls (OR = 1.96, 95% confidence interval 0.91-4.23; -value = 0.0552). Genotype frequencies did not show any significant difference between patients and controls. The homozygous TT genotype was observed in 2% of endometriosis women and not in controls.

Conclusions: Our results show that the rs4986791 T variant may be considered a genetic risk factor for endometriosis in Italian women. More extensive studies in other populations are needed to confirm this result.
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http://dx.doi.org/10.3390/diagnostics10050255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277393PMC
April 2020

BET inhibition therapy counteracts cancer cell survival, clonogenic potential and radioresistance mechanisms in rhabdomyosarcoma cells.

Cancer Lett 2020 06 19;479:71-88. Epub 2020 Mar 19.

Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy. Electronic address:

The antitumour effects of OTX015, a first-in-class BET inhibitor (BETi), were investigated as a single agent or in combination with ionizing radiation (IR) in preclinical in vitro models of rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma. Herein, we demonstrated the upregulation of BET Bromodomain gene expression in RMS tumour biopsies and cell lines compared to normal skeletal muscle. In vitro experiments showed that OTX015 significantly reduced RMS cell proliferation by altering cell cycle modulators and apoptotic related proteins due to the accumulation of DNA breaks that cells are unable to repair. Interestingly, OTX015 also impaired migration capacity and tumour-sphere architecture by downregulating pro-stemness genes and was able to potentiate ionizing radiation effects by reducing the expression of different drivers of tumour dissemination and resistance mechanisms, including the GNL3 gene, that we correlated for the first time with the RMS phenotype. In conclusion, our research sheds further light on the molecular events of OTX015 action against RMS cells and indicates this novel BETi as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with RMS.
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http://dx.doi.org/10.1016/j.canlet.2020.03.011DOI Listing
June 2020

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1.

Am J Med Genet A 2020 03 27;182(3):508-512. Epub 2019 Dec 27.

Medical Genetics Unit, Casa Sollievo della Sofferenza IRCCS Foundation, San Giovanni Rotondo, Italy.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss-of-function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC-1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease-alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting.
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http://dx.doi.org/10.1002/ajmg.a.61431DOI Listing
March 2020
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