Publications by authors named "Laura Bernardini"

109 Publications

Generation of an induced pluripotent stem cell line (CSS012-A (7672)) carrying the p.G376D heterozygous mutation in the TARDBP protein.

Stem Cell Res 2021 May 18;53:102356. Epub 2021 Apr 18.

Cellular Reprogramming Unit, Fondazione I.R.C.C.S. Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative condition with phenotypic and genetic heterogeneity. It is characterized by the selective vulnerability and the progressive loss of the neural population. Here, an induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of an individual carrying the p.G376D mutation in the TDP-43 protein. Fibroblasts were reprogrammed using non-integrating episomal plasmids. There were no karyotype abnormalities, and iPSCs successfully differentiated into all three germ layers. This cell line may prove useful in the study of the pathogenic mechanisms that underpin ALS syndrome.
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http://dx.doi.org/10.1016/j.scr.2021.102356DOI Listing
May 2021

Equivalent Efficacy but Different Safety Profiles of Gemcitabine Plus Nab-Paclitaxel and FOLFIRINOX in Metastatic Pancreatic Cancer.

Biomolecules 2021 May 22;11(6). Epub 2021 May 22.

Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.

FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN) are the most common chemotherapy regimens in first-line treatment of metastatic pancreatic cancer (PC). They have not been compared each other in a prospective trial, but only in retrospective studies, which can thus be affected by several biases. In order to overcome these biases, we took advantage of matching-adjusted indirect comparison (MAIC), that allows an indirect comparison by reducing cross-trial differences, and compared data from 268 patients treated with GN in a real-world setting with data from the 171 patients included in the FFX arm of the PRODIGE trial. Survival outcomes did not differ between the two populations. Overall survival was 11.1 months for both treatments (hazard ratio (HR) of FFX 1.10, 95% confidence interval (CI) 0.81-1.49; = 0.527). Progression-free survival was 6.0 months with GN and 6.4 months with FFX (HR of FFX 1.11, 95% CI 0.82-1.50; = 0.520). On the other hand, we observed a difference in the toxicity profiles: grade 3/4 anemia was more frequent with GN, whereas a higher occurrence of grade 3/4 vomiting and diarrhea was reported with FFX. FFX and GN show an equivalent efficacy but different safety profiles in the first-line therapy of metastatic pancreatic cancer. Searching for reliable predictive biomarkers is advised in order to improve therapeutic strategy in metastatic PC.
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http://dx.doi.org/10.3390/biom11060780DOI Listing
May 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
May 2021

A Novel Prognostic Tool in Western and Eastern Biliary Tract Cancer Patients Treated in First-line Setting: the ECSIPOT Index.

J Gastrointest Cancer 2021 May 25. Epub 2021 May 25.

School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

Background And Aim: The need to estimate prognosis of advanced BTC (aBTC) patients treated with first-line chemotherapy is compelling. The aim of the study is to evaluate the ECSIPOT (psECogSIiPnigOT) index, influenced by PECS (PsECogSii) index, prognostic nutritional index (PNI), and GOT.

Methods: This international study was conducted on a training cohort of 126 patients and in three validation cohorts, both European and Korean. ECSIPOT index formula: (PECS:0 = 1 point; PECS:1 = 1.4 points; PECS:2 = 3.2 points) + (PNI > 36.7 = 1 point; PNI < 36.7 = 2 points) + (GOT < 100 = 1 point; GOT > 100 = 2 points). Event-time distributions were estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test.

Results: In the training cohort, mOS was 12.9, 6.3, and 2.8 months for patients with ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 2.11; ECSIPOT-2: HR 4.93; p < 0.0001). In the first validation cohort, mOS was 11.5, 7.3, and 3.3 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 1.74; ECSIPOT-2: HR 3.41; p < 0.0001). In the second validation cohort, mOS was 25.2, 12.5, and 3.0 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 2.33; ECSIPOT-2: HR 8.46; p < 0.0001). In the third validation cohort, mOS was 11.8, 8.1, and 4.6 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 1.47; ECSIPOT-2: HR 3.17; p < 0.0001). Multivariate analysis in all cohorts confirmed the ECSIPOT index as an independent prognostic factor for OS.

Conclusion: The easy assessment and good risk-stratification performance make the ECSIPOT index a promising tool to comprehensively estimate the prognosis of aBTC patients.
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http://dx.doi.org/10.1007/s12029-021-00649-3DOI Listing
May 2021

Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects.

Clin Genet 2021 May 14. Epub 2021 May 14.

Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Rome, Italy.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.
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http://dx.doi.org/10.1111/cge.13994DOI Listing
May 2021

Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients.

Oncology 2021 24;99(5):292-299. Epub 2021 Feb 24.

IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

Background And Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications.

Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics.

Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016).

Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.
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http://dx.doi.org/10.1159/000512796DOI Listing
May 2021

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS).

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Istituto Auxologico Italiano IRCCS, Bioinformatics and Statistical Genomics Unit, Cusano Milanino, 20095 Milano, Italy.

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. , , and gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.
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http://dx.doi.org/10.3390/ijms22031190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866060PMC
January 2021

Autism and severe clinical phenotype in a patient with 8p21.2p11.21 deletion: Case report and literature review.

Clin Case Rep 2021 Jan 12;9(1):314-321. Epub 2020 Nov 12.

Victor Babes National Institute of Pathology Bucharest Romania.

Interstitial 8p deletions were previously described, in literature and databases, in approximately 30 patients with neurodevelopmental disorders. We report on a novel patient with a 8p21.2p11.21 deletion presenting a clinical phenotype that includes severe intellectual disability, microcephaly, epilepsy, and autism, the latter having been rarely associated with this genetic defect.
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http://dx.doi.org/10.1002/ccr3.3523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813129PMC
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 Jan 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

COVID-19: neonatal-perinatal perspectives.

J Perinatol 2021 05 8;41(5):940-951. Epub 2020 Dec 8.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The coronavirus disease 2019 (COVID-19) pandemic, resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused severe and widespread illness in adults, including pregnant women, while rarely infecting neonates. An incomplete understanding of disease pathogenesis and viral spread has resulted in evolving guidelines to reduce transmission from infected mothers to neonates. Fortunately, the risk of neonatal infection via perinatal/postnatal transmission is low when recommended precautions are followed. However, the psychosocial implications of these practices and racial/ethnic disparities highlighted by this pandemic must also be addressed when caring for mothers and their newborns. This review provides a comprehensive overview of neonatal-perinatal perspectives of COVID-19, ranging from the basic science of infection and recommendations for care of pregnant women and neonates to important psychosocial, ethical, and racial/ethnic topics emerging as a result of both the pandemic and the response of the healthcare community to the care of infected individuals.
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http://dx.doi.org/10.1038/s41372-020-00874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721617PMC
May 2021

Identification of a De Novo Xq26.2 Microduplication Encompassing Gene in a Child with Intellectual Disability.

Diagnostics (Basel) 2020 Nov 25;10(12). Epub 2020 Nov 25.

Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.

Long non-coding RNAs (lncRNAs), defined as transcripts of >200 nucleotides not translated into protein, have been involved in a wide range of regulatory functions. Their dysregulations have been associated with diverse pathological conditions such as cancer, schizophrenia, Parkinson's, Huntington's, Alzheimer's diseases and Neurodevelopmental Disorders (NDDs), including autism spectrum disorders (ASDs). We report on the case of a five-year-old child with global developmental delay carrying a de novo microduplication on chromosome Xq26.2 region characterized by a DNA copy-number gain spanning about 147 Kb (chrX:130,813,232-130,960,617; GRCh37/hg19). This small microduplication encompassed the exons 2-12 of the functional intergenic repeating RNA element ( gene (chrX:130,836,678-130,964,671; GRCh37/hg19) that encodes for a lncRNA involved in the maintenance of chromatin repression. The association of such a genetic alteration with a severe neurodevelopmental delay without clear dysmorphic features and congenital abnormalities indicative of syndromic condition further suggests that small Xq26.2 chromosomal region microduplications containing the gene may be responsible for clinical phenotypes mainly characterized by structural or functioning neurological impairment.
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http://dx.doi.org/10.3390/diagnostics10121009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760855PMC
November 2020

Impact of Aspirin on clinical outcome in advanced HCC patients receiving sorafenib and regorafenib.

HPB (Oxford) 2021 Jun 12;23(6):915-920. Epub 2020 Nov 12.

Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy.

Background And Aim: The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib.

Methods: 304 patients with HCC,consecutively treated with sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02).

Conclusion: Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.
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http://dx.doi.org/10.1016/j.hpb.2020.09.024DOI Listing
June 2021

First-line gemcitabine plus nab-paclitaxel for elderly patients with metastatic pancreatic cancer: Crossing the frontier of age?

Eur J Cancer 2020 09 1;137:108-116. Epub 2020 Aug 1.

Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, Pisa, 56126, Italy. Electronic address:

Background: Gemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population.

Methods: We collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: <70 (group 1: 65 patients) and ≥70 years (group 2: 91 patients).

Results: The median age was 71 years (range: 65-87 years). The toxicity profile was similar between group 1 and 2, except for all-grade anaemia (92.1% vs. 78.7%, respectively; p = 0.04) and neurotoxicity (61.9% vs. 40.4%, respectively; p = 0.02), also as a result of a lower dose intensity of nab-paclitaxel (83.3% vs. 90.5%, respectively; p = 0.04) administered to oldest patients. The response rate was 25.6% (group 1 vs. 2: 20.0% vs. 29.7%; p = 0.12). After a median follow-up of 26.5 months, median overall survival (OS) and progression-free survival (PFS) were similar between the groups (p > 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05).

Conclusion: Gem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.
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http://dx.doi.org/10.1016/j.ejca.2020.06.031DOI Listing
September 2020

Generation of an induced pluripotent stem cell line, CSSi011-A (6534), from an Amyotrophic lateral sclerosis patient with heterozygous L145F mutation in SOD1 gene.

Stem Cell Res 2020 Jul 25;47:101924. Epub 2020 Jul 25.

Fondazione IRCCS Casa Sollievo della Sofferenza, Cellular Reprogramming Unit - Viale dei Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

Among the known causative genes of familial ALS, SOD1mutation is one of the most common. It encodes for the ubiquitous detoxifying copper/zinc binding SOD1 enzyme, whose mutations selectively cause motor neuron death, although the mechanisms are not as yet clear. What is known is that mutant-mediated toxicity is not caused by loss of its detoxifying activity but by a gain-of-function. In order to better understand the pathogenic mechanisms of SOD1 mutation, a human induced pluripotent stem cell (hiPSC) line was generated from the somatic cells of a female patient carrying a missense variation in SOD1 (L145F).
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http://dx.doi.org/10.1016/j.scr.2020.101924DOI Listing
July 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

Further delineation of the neurodevelopmental phenotypic spectrum associated to 14q11.2 microduplication.

Neurol Sci 2020 12 11;41(12):3751-3753. Epub 2020 Jun 11.

Medical Genetics Laboratory, Clinical Genetics Division, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense 87, 00152, Rome, Italy.

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http://dx.doi.org/10.1007/s10072-020-04510-6DOI Listing
December 2020

Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism.

Parkinsonism Relat Disord 2020 03 15;72:75-79. Epub 2020 Feb 15.

Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy; IRCCS Neuromed, Pozzilli, IS, Italy.

Objective: To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants.

Methods: A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes.

Results: WES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function.

Conclusion: Our findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.
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http://dx.doi.org/10.1016/j.parkreldis.2020.02.003DOI Listing
March 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

ALK-negative anaplastic large cell lymphoma with "Hodgkin-like" cytomorphology and nuclear expression of PAX5.

Pathol Res Pract 2020 Feb 31;216(2):152724. Epub 2019 Oct 31.

Hematology Unit, Saint' Eugenio Hospital, Rome, Italy.

Anaplastic lymphoma kinase negative systemic anaplastic large cell lymphoma (ALK-ALCL) is a CD30+ T-cell malignant lymphoma which may involve both lymph nodes and extranodal tissues, showing important clinical differences from ALK-positive ALCL (ALK + ALCL). ALK- ALCL is considered a specific entity by the 2016 World Health Organization (WHO) classification of hematolymphoid neoplasms.We describe an exceptional case of ALK- ALCL with a striking "Hodgkin-like" cytomorphology and a very uncommon nuclear expression of PAX5.
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http://dx.doi.org/10.1016/j.prp.2019.152724DOI Listing
February 2020

Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation.

Mol Genet Genomic Med 2020 01 22;8(1):e1054. Epub 2019 Nov 22.

Fondazione IRCCS Casa Sollievo della Sofferenza, Laboratory of Clinical Genomics, San Giovanni Rotondo (FG), Italy.

Background: Posterior fossa malformations are among the most diagnosed central nervous system (CNS) anomalies detected by ultrasound (US) in prenatal age. We identified the pathogenic gene mutation in a male fetus of 17 weeks of gestation with US suspicion of familial Dandy-Walker spectrum malformation, using Next Generation Sequencing approach in prenatal diagnosis.

Methods: Whole exome sequencing (WES) approach has been performed on fetal genomic DNA. After reads preprocessing, mapping, variant calling, and annotation, a filtering strategy based on allelic frequency, recessive inheritance, and phenotypic ontologies has been applied. A fetal magnetic resonance imaging (MRI) at 18 weeks of gestation has been performed. An in silico analysis of a potential causative missense variant in the fukutin protein has been carried out through a structural modeling approach.

Results: We identified a new homozygous missense mutation in fukutin gene (FKTN, NM_006731.2: c.898G>A; NP_006722.2: p.Gly300Arg). Fetal MRI supported molecular findings. Structural modeling analyses indicated a potential pathogenetic mechanism of the variant, through a reduced activation of the sugar moieties, which in turn impairs transfer to dystroglycan and thus its glycosylation. These findings pointed to a redefinition of the US suspicion of recurrence of Dandy-Walker malformation (DWM) to a muscular dystrophy-dystroglycanopathy type A4.

Conclusions: The present case confirmed WES as a reliable tool for the prenatal identification of the molecular bases of early-detected CNS malformations.
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http://dx.doi.org/10.1002/mgg3.1054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978243PMC
January 2020

A novel developmental encephalopathy with epilepsy and hyperkinetic movement disorders associated with a deletion of the sodium channel gene cluster on chromosome 2q24.3.

Parkinsonism Relat Disord 2019 11 18;68:1-3. Epub 2019 Sep 18.

Division of Child Neurology and Infantile Psychiatry, Department of Neuroscience, Sapienza University of Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2019.09.016DOI Listing
November 2019

Small 7p22.3 microdeletion: Case report of Snx8 haploinsufficiency and neurological findings.

Eur J Med Genet 2020 Apr 27;63(4):103772. Epub 2019 Sep 27.

Department of Experimental Medicine, Policlinico Umberto I Hospital, Sapienza University of Rome, Viale Regina Elena 324, Rome, Italy; Medical Genetics Unit, IRCCS Mendel Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy. Electronic address:

Some cases of chromosome 7p22.3 deletions have been reported, but the genotype-phenotype correlation is still uncertain. Neurodevelopmental delay and heart anomalies have been recorded as the most recurrent defects. We describe the clinical features of a four-year-old male child with a 139 kb deletion at 7p22.3 involving SNX8 gene, inherited from a mosaic mother. The same deletion is also present in the fetus on the ongoing third pregnancy of the couple with normal fetal ultrasound assessment. The proband was prenatally diagnosed with left kidney agenesis. He does not show any congenital heart disease, but mild intellectual disability, learning and language delay, and severe behavioral problems related to the hyperactive-impulsive and inattentive area. These clinical features are also evident in other 7p22 deletions cases involving the SNX8 gene, supporting the role of this gene in neurodevelopment. Conversely, the revision of all published cases with small 7p22 deletions and the absence of heart malformations in the present family confirm that this region is involved in heart development, anyway did not confirm the role of SNX8 in cardiac phenotypes, either due to the reduced penetrance or the involvement of other candidate genes.
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http://dx.doi.org/10.1016/j.ejmg.2019.103772DOI Listing
April 2020

Generation of induced pluripotent stem cell line CSSi008-A (4698) from a patient affected by advanced stage of Dentato-Rubral-Pallidoluysian atrophy (DRPLA).

Stem Cell Res 2019 10 27;40:101551. Epub 2019 Aug 27.

Fondazione IRCCS Casa Sollievo della Sofferenza, Cellular Reprogramming Unit, Viale dei Cappuccini, 71013, San Giovanni Rotondo, Foggia, Italy. Electronic address:

Dentato-Rubral-pallidoluysian atrophy (DRPLA) is a rare autosomal, dominant, progressive neurodegenerative disease that causes involuntary movements, mental and emotional problems. DRPLA is caused by a mutation in the ATN1 gene that encodes for an abnormal polyglutamine stretch in the atrophin-1 protein. DRPLA is most common in the Japanese population, where it has an estimated incidence of 2 to 7 per million people. This condition has also been seen in families from North America and Europe. We obtained a reprogrammed iPSC line from a Caucasian patient with a juvenile onset of the disease, carrying 64 CAG repeat expansion in the ATN1 gene.
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http://dx.doi.org/10.1016/j.scr.2019.101551DOI Listing
October 2019

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Hum Mutat 2020 01 14;41(1):150-168. Epub 2019 Nov 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.
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http://dx.doi.org/10.1002/humu.23902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953250PMC
January 2020

A novel mosaic 1q32.1 microduplication identified through Chromosome Microarray Analysis: narrowing the smallest critical region including KDM5B gene found associated with neurodevelopmetal disorders.

Eur J Med Genet 2019 Sep 25;62(9):103558. Epub 2018 Oct 25.

Fondazione IRCCS Casa Sollievo Della Sofferenza, Cytogenetics Unit, San Giovanni Rotondo (FG), Italy.

Microduplications involving 1q32.1 chromosomal region have been rarely reported in literature. Patients with these microduplications suffer from intellectual disability, developmental delay and a number of dysmorphic features, although no clear karyotype/phenotype correlation has yet been determined. In this case report we describe two monochorionic-diamniotic twins with intellectual disability, abnormality of coordination and dysmorphic features associated with a de novo 280 kb mosaic microduplication of 1q32.1 chromosomal region, identified using a Chromosome Microarray Analysis (CMA) and confirmed by quantitative PCR analysis. The duplicated region encompassed entirely three OMIM genes KDM5B (*605393), KLHL12 (*614522), RABIF (*603417) and involved partially SYT2 (*600104). This unique case report allows to redefine the critical 1q32.1 microduplicated region implicated in the ethiopathogenesis of intellectual disability and developmental delay. Furthermore, it suggests that KDM5B gene can have a pivotal role in the development of neurodevelopmental disorders through its demethylase activity.
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http://dx.doi.org/10.1016/j.ejmg.2018.10.010DOI Listing
September 2019

Production and characterization of human induced pluripotent stem cells (iPSC) CSSi007-A (4383) from Joubert Syndrome.

Stem Cell Res 2019 07 5;38:101480. Epub 2019 Jun 5.

Fondazione IRCCS Casa Sollievo della Sofferenza, Cellular Reprogramming Unit, Viale dei Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.
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http://dx.doi.org/10.1016/j.scr.2019.101480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617992PMC
July 2019

Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome.

Stem Cells Transl Med 2019 09 18;8(9):887-897. Epub 2019 May 18.

Eastern Piedmont University, "Maggiore della Carità" Hospital, Dipartimento di Neurologia, Novara.

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&897.
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http://dx.doi.org/10.1002/sctm.18-0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708070PMC
September 2019

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Clin Genet 2019 09 17;96(3):246-253. Epub 2019 Jun 17.

Medical Genetics Unit, Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo (FG), Italy.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
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http://dx.doi.org/10.1111/cge.13565DOI Listing
September 2019

Epilepsy phenotype in patients with Xp22.31 microduplication.

Epilepsy Behav Case Rep 2019 4;11:31-34. Epub 2018 Nov 4.

Department of Human Neurosciences, Sapienza University of Rome, Italy.

The clinical significance of Xp22.31 microduplication is still unclear. We describe a family in which a mother and two children have Xp22.31 microduplication associated with different forms of epilepsy and epileptiform EEG abnormalities. The proband had benign epilepsy with centrotemporal spikes with dysgraphia and dyscalculia (IQ 72), the sister had juvenile myoclonic epilepsy, and both had bilateral talipes anomalies. The mother, who was the carrier of the microduplication, was asymptomatic. The asymptomatic father did not possess the microduplication. These data contribute to delineate the phenotype associated with Xp22.31 microduplication and suggest a potential pathogenic role for an epilepsy phenotype.
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http://dx.doi.org/10.1016/j.ebcr.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310737PMC
November 2018