Publications by authors named "Sabrina Giglio"

85 Publications

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice.

Nephrol Dial Transplant 2021 Jul 15. Epub 2021 Jul 15.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Germany.

The overall diagnostic yield of massively parallel sequencing (MPS) based-tests in patients with chronic kidney disease (CKD) is around 30% for pediatric cases and 6-30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients, but in reality several barriers appear to hinder the implementation of NGS diagnostics in routine clinical practice. In this paper, we aim to support the nephrologist to overcome these barriers. After a detailed discussion on the general items that are important to genetic testing in nephrology, namely (1) genetic testing modalities and their indications, (2) clinical information needed for high-quality interpretation of the genetic test, (3) clinical benefit of genetic testing and (4) genetic counselling, we will describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.
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http://dx.doi.org/10.1093/ndt/gfab218DOI Listing
July 2021

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

Seizure 2021 May 30;88:60-72. Epub 2021 Mar 30.

Maternal and Pediatric Department, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio "Giovanni Paolo II", Viale Padre Pio, snc, San Giovanni Rotondo (FG) 71013, Italy.

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".

Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.

Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
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http://dx.doi.org/10.1016/j.seizure.2021.03.025DOI Listing
May 2021

Distal renal tubular acidosis: a systematic approach from diagnosis to treatment.

J Nephrol 2021 Mar 26. Epub 2021 Mar 26.

Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Renal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO is impaired, leading to chronic metabolic acidosis with normal anion gap. In the current review, the focus is placed on the most common type of RTA, Type 1 RTA or Distal RTA (dRTA), which is a rare chronic genetic disorder characterized by an inability of the distal nephron to secrete hydrogen ions in the presence of metabolic acidosis. Over the years, knowledge of the molecular mechanisms behind acid secretion has improved, thereby greatly helping the diagnosis of dRTA. The primary or inherited form of dRTA is mostly diagnosed in infancy, childhood, or young adulthood, while the acquired secondary form, as a consequence of other disorders or medications, can happen at any age, although it is more commonly seen in adults. dRTA is not as "benign" as previously assumed, and can have several, highly variable long-term consequences. The present review indeed reports and summarizes both clinical symptoms and diagnosis, long-term outcomes, genetic inheritance, epidemiology and current treatment options, with the aim of shedding more light onto this rare disorder. Being a chronic condition, dRTA also deserves attention in the transition between pediatric and adult nephrology care, and as a rare disease it has a place in the European and Italian rare nephrological diseases network.
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http://dx.doi.org/10.1007/s40620-021-01032-yDOI Listing
March 2021

Leopard-like retinopathy and severe early-onset portal hypertension expand the phenotype of KARS1-related syndrome: a case report.

BMC Med Genomics 2021 01 21;14(1):25. Epub 2021 Jan 21.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Background: Mutations in lysyl-tRNA synthetase (KARS1), an enzyme that charges tRNA with the amino acid lysine in both the cytoplasm and mitochondria, have been associated thus far with autosomal recessive Charcot-Marie-Tooth type CMTRIB, hearing loss type DFNB89, and mitochondrial encephalohepatopathy (MEH) featuring neurodevelopmental disorders with microcephaly, white matter changes, and cardiac and hepatic failure in less than 30 patients.

Case Presentation: We report the clinical, biochemical and molecular findings of a 14-month-old girl with severe MEH compatible clinical features, profound sensorineural hearing loss, leopard spot retinopathy, pancytopenia, and advanced liver disease with portal hypertension leading to death at the age of 30 months.

Conclusions: Whole exome sequencing identified two rare variants in KARS1 gene. Our report expands the allelic and clinical features of tRNA synthase disorders. Moreover, with our report we confirm the usefulness of WES as first tier diagnostic method in infants with complex multisystem phenotypes.
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http://dx.doi.org/10.1186/s12920-020-00863-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818779PMC
January 2021

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

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

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

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

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

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

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Hum Genet 2021 Apr 18;140(4):625-647. Epub 2020 Dec 18.

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

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.
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http://dx.doi.org/10.1007/s00439-020-02231-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981314PMC
April 2021

A novel stop codon variant affecting ΔNp63 isoforms associated with non-syndromic limb-mammary phenotype and uterine cervix dysplasia.

Clin Genet 2021 Mar 1;99(3):486-487. Epub 2020 Dec 1.

DINOGMI, University of Genova - UOC Genetica Medica IRCCS Giannina Gaslini, Genoa, Italy.

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http://dx.doi.org/10.1111/cge.13889DOI Listing
March 2021

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Disseminated Mycobacterium xenopi in an Adult with IL-12Rβ1 Deficiency.

J Clin Immunol 2020 11 27;40(8):1166-1170. Epub 2020 Aug 27.

Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, FI, Italy.

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http://dx.doi.org/10.1007/s10875-020-00848-wDOI Listing
November 2020

Genetic counseling during COVID-19 pandemic: Tuscany experience.

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

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

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

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

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

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

Variable clinical expression of Stickler Syndrome: A case report of a novel COL11A1 mutation.

Mol Genet Genomic Med 2020 09 17;8(9):e1353. Epub 2020 Jun 17.

Department of Rare Skeletal Disorders & CLIBI Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Background: Stickler Syndrome is a rare connective tissue disorder, characterized by clinical, and genetic heterogeneity. The clinical expression is highly variable, including moderate to severe myopia in childhood, hearing loss, facial dysmorphic features, cleft palate, and early osteoarthritis. COL2A1, COL11A1, and COL11A2 mutations account of the majority of autosomal dominant Stickler Syndrome and, in particular, a heterozygous mutation in COL11A1 gene is identified in about 10 to 20% of Stickler Syndrome patients.

Methods: Herein, we report a case of an 8-year- old child with Stickler Syndrome, presenting with early-onset of myopia with vitreal abnormalities, facial dysmorphic characteristics, and mild hearing loss later in childhood. To identify the underlying genetic cause, Whole Exome Sequencing was carried out for COL11A1 gene.

Results: A novel de novo heterozygous splice site variant (NM_001854: c.1845 + 5G> C) of the COL11A1 gene, which had not been previously reported, was identified by Whole Exome Sequencing.

Conclusion: We reported a novel COL11A1 mutation in a child with Stickler Syndrome presenting a phenotype of early-onset of ocular anomalies and mild hearing loss later in childhood. Our findings confirm the variability of the expression of the disease, even in the contest of the same gene-related disorder, thus, contributing to improve the knowledge on clinical and molecular basis of this rare disease.
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http://dx.doi.org/10.1002/mgg3.1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507508PMC
September 2020

Noninvasive prenatal diagnosis in a family at risk for Fraser syndrome.

Prenat Diagn 2020 06 20;40(7):905-908. Epub 2020 Apr 20.

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

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http://dx.doi.org/10.1002/pd.5700DOI Listing
June 2020

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.

Sci Transl Med 2020 03;12(536)

Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
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http://dx.doi.org/10.1126/scitranslmed.aaw6003DOI Listing
March 2020

Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder.

J Med Genet 2020 11 13;57(11):760-768. Epub 2020 Mar 13.

Division of Medical Genetics, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

Background: The regulation of the chromatin state by epigenetic mechanisms plays a central role in gene expression, cell function, and maintenance of cell identity. Hereditary disorders of chromatin regulation are a group of conditions caused by abnormalities of the various components of the epigenetic machinery, namely writers, erasers, readers, and chromatin remodelers. Although neurological dysfunction is almost ubiquitous in these disorders, the constellation of additional features characterizing many of these genes and the emerging clinical overlap among them indicate the existence of a community of syndromes. The introduction of high-throughput next generation sequencing (NGS) methods for testing multiple genes simultaneously is a logical step for the implementation of diagnostics of these disorders.

Methods: We screened a heterogeneous cohort of 263 index patients by an NGS-targeted panel, containing 68 genes associated with more than 40 OMIM entries affecting chromatin function.

Results: This strategy allowed us to identify clinically relevant variants in 87 patients (32%), including 30 for which an alternative clinical diagnosis was proposed after sequencing analysis and clinical re-evaluation.

Conclusion: Our findings indicate that this approach is effective not only in disorders with locus heterogeneity, but also in order to anticipate unexpected misdiagnoses due to clinical overlap among cognate disorders. Finally, this work highlights the utility of a prompt diagnosis in such a clinically and genetically heterogeneous group of disorders that we propose to group under the umbrella term of chromatinopathies.
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http://dx.doi.org/10.1136/jmedgenet-2019-106724DOI Listing
November 2020

Clinical correlates in children with autism spectrum disorder and CNVs: Systematic investigation in a clinical setting.

Int J Dev Neurosci 2020 Jun 25;80(4):276-286. Epub 2020 Mar 25.

Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Autism spectrum disorder (ASD) is associated with various molecular mechanisms including copy number variants (CNVs). We investigated possible associations between CNVs and ASD clinical correlates. We evaluated pertinent physical characteristics and phenotypic measures such as cognitive level, severity of ASD symptoms and comorbid conditions in ASD patients consecutively recruited over the study period. Children with causative (C-CNVs), non-causative (NC-CNVs) and without CNVs (W-CNVs) were compared. Out of 109 patients, 31 imbalances (16 duplications and 15 deletions) were detected in 25 subjects. Seven (6.4%) had C-CNVs and 18 (16.5%) had NC-CNVs. Paired post hoc comparisons with Bonferroni adjustment showed that dysmorphisms and microcephaly were significantly more frequent in the C-CNVs group. Patients with C-CNVs had more severe autistic core symptoms, while comorbid internalizing behavioral symptoms were more represented among participants with NC-CNVs. No significant differences were observed for distribution of macrocephaly, intellectual disability, epilepsy, isolated electroencephalogram abnormalities and studied neuroimaging characteristics among groups. Recurrent and rare C-CNVs highlighting genes relevant to neurodevelopment had a statistically higher occurrence in children with more severe ASD symptoms and further developmental abnormalities. This study documents the importance of measuring the physical and neurobehavioural correlates of ASD phenotypes to unravel the underlying molecular mechanisms in patient subgroups.
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http://dx.doi.org/10.1002/jdn.10024DOI Listing
June 2020

Novel mutations in and are associated with posterior microphthalmos.

Ophthalmic Genet 2020 02 2;41(1):49-56. Epub 2020 Mar 2.

Pediatric Ophthalmology Unit, A. Meyer Children's Hospital, Firenze, Italy.

: Biallelic pathogenic variants in and genes can be responsible for nanophthalmos (NO) or posterior microphthalmos (PM). This study describes detailed clinical and molecular findings in a series of five patients affected by PM from four unrelated families.: All patients underwent a complete ophthalmological and genetic evaluation. For proper and deep phenotyping a multimodal instrumental approach was used for all cases: B-scan ultrasound, spectral domain optical coherence tomography (SD-OCT), fundus retinal imaging and anterior segment data were obtained. Molecular analysis of and genes was performed with Next-Generation Sequencing (NGS) methodology and segregation analysis on parents and one affected sibling was performed with Sanger sequencing.: A very high hyperopia of +14.00D or more was the main refractive error and macular abnormalities were identified in all patients. Axial length ranged from 15.3 mm to 17.86 mm (mean 16.58 mm) and age at first presentation ranged from 6 to 36 months (mean 18 months). Anterior chamber depth was within normal values, according to age, while total axial length was severely reduced in all patients. All our patients met the diagnostic criteria for PM. Three patients, including a pair of siblings, carried compound heterozygous mutations in the gene; in the other two patients, one homozygous or two compound heterozygous mutations in the gene were detected.: Our study describes four novel mutations in the gene and one in the gene in patients with non-syndromic posterior microphthalmos. Proper genotype-phenotype correlation and early diagnosis could lead to good functional results.
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http://dx.doi.org/10.1080/13816810.2020.1731835DOI Listing
February 2020

Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.

Clin J Am Soc Nephrol 2020 01 12;15(1):89-100. Epub 2019 Dec 12.

Department of Clinical and Experimental Biomedical Sciences "Mario Serio,"

Background And Objectives: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.

Design, Setting, Participants, & Measurements: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.

Results: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.

Conclusions: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.
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http://dx.doi.org/10.2215/CJN.06060519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946071PMC
January 2020

Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition.

Clin Genet 2019 10 15;96(4):359-365. Epub 2019 Jul 15.

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

Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer-related genes in 50% of patients undergoing array-CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low-grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.
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http://dx.doi.org/10.1111/cge.13600DOI Listing
October 2019

A microRNA profile of pediatric glioblastoma: The role of NUCKS1 upregulation.

Mol Clin Oncol 2019 Mar 2;10(3):331-338. Epub 2019 Jan 2.

Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's University Hospital, I-50139 Florence, Italy.

MicroRNAs (miRNAs/miRs) are a novel class of gene regulators that may be involved in tumor chemoresistance. Recently, specific miRNA expression profiles have been identified in adult glioblastoma (aGBM), but there are only limited data available on the role of miRNAs in pediatric GBM (pGBM). In the present study, the expression profile of miRNAs was examined in seven pGBMs and three human GBM cell lines (U87MG, A172 and T98G), compared with a non-tumoral pool of pediatric cerebral cortex samples by microarray analysis. A set of differentially expressed miRNAs was identified, including miR-490, miR-876-3p, miR-876-5p, miR-448 and miR-137 (downregulated), as well as miR-501-3p (upregulated). Through bioinformatics analysis, a series of target genes was predicted. In addition, similar gene expression patterns in pGBMs and cell lines was confirmed. Of note, drug resistant T98G cells had upregulated nuclear casein kinase and cyclin-dependent kinase substrate 1 () expression, a protein overexpressed in many tumors that serves an important role in cell proliferation and progression. On the basis of the present preliminary report, it could be intriguing to further investigate the relationship between each of the identified differentially expressed miRNAs and NUCKS1, in order to clarify their involvement in the multi-drug resistance mechanism of pGBMs.
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http://dx.doi.org/10.3892/mco.2019.1795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388501PMC
March 2019

[A child with severe growth delay and renal cysts].

G Ital Nefrol 2019 Feb;36(1)

UO Genetica Medica, Ospedale Meyer Firenze.

We describe the case of a 5-year-old who came to our attention for a growth delay. Among the investigations planned because of the child's short stature, we performed an abdominal ultrasound showing normal-sized kidneys with signs of cortico-medullar de-differentiation, diffuse medullary hyperechogenicity with reduction of cortical thickness and cortical-medullary cysts. The ultrasound findings, also confirmed in MRI, led us to suspect a genetically determined cystic nephropathy of the nephronophthisis or medullary cystic disease type. No mutation was identified in NPHP1, HNFb1 and UMOD genes. Interestingly, laboratory investigations revealed a severe metabolic acidosis with normal renal function and hypokalemia. These findings are not characteristics of a nephronophthisis. We therefore also performed molecular analysis for distal tubular acidosis (dRTA) that showed the association of two genetic variants of ATP6V1B1 and SLC4A genes. These "double mutations" have been inherited from the mother, which however does not have the classic dRTA phenotype. These variants do not currently meet the criteria for a conclusive molecular diagnosis of dRTA but represent variants of uncertain clinical significance. However, considering the clinical and laboratory data one can reasonably conclude that the child has a "probable" diagnosis of distal tubular acidosis. The rapid recovery of staturo-ponderal growth after the start of alkalizing treatment supports our diagnostic hypothesis. The association between distal tubular acidosis and renal cysts is well described in the literature. The hypothesis is that chronic hypokalemia may play a possible role in the formation of renal cysts.
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February 2019

Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review.

BMC Cancer 2019 Jan 31;19(1):113. Epub 2019 Jan 31.

Department of Neuroscience, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy.

Background: Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.

Methods: The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement.

Results: In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers.

Conclusions: Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context.

Trial Registration: Registration number: CRD42017057831 .
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http://dx.doi.org/10.1186/s12885-019-5310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357360PMC
January 2019

Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity.

Eur J Hum Genet 2019 06 25;27(6):909-918. Epub 2019 Jan 25.

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.

Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P < 0.05) overrepresentation of genes involved in vesicle-mediated transport. Rare genomic imbalances, either small CNVs or large rearrangements, are cumulatively a frequent cause of PNH. Dysregulation of specific cellular mechanisms might play a key pathogenic role in PNH but it remains to be determined whether this is exerted through single genes or the cumulative dosage effect of more genes. Array-CGH should be considered as a first-line diagnostic test in PNH, especially if sporadic and non-classical.
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http://dx.doi.org/10.1038/s41431-019-0335-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777581PMC
June 2019

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

Hum Mutat 2019 02 22;40(2):193-200. Epub 2018 Nov 22.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis.
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http://dx.doi.org/10.1002/humu.23683DOI Listing
February 2019

De novo unbalanced translocations have a complex history/aetiology.

Hum Genet 2018 Oct 1;137(10):817-829. Epub 2018 Oct 1.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.
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http://dx.doi.org/10.1007/s00439-018-1941-9DOI Listing
October 2018

Bicuspid Aortic Valve: Role of Multiple Gene Variants in Influencing the Clinical Phenotype.

Biomed Res Int 2018 5;2018:8386123. Epub 2018 Sep 5.

Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy.

Bicuspid aortic valve (BAV) is a common congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant pattern of inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with other clinical manifestations in syndromic conditions. Identification of a syndromic condition in a BAV patient is clinically relevant in order to personalize indication to aortic surgery. We aimed to point out how genetic diagnosis by next-generation sequencing (NGS) can improve management of a patient with complex BAV clinical picture. We describe a 45-year-old Caucasian male with BAV, thoracic aortic root and ascending aorta dilatation, and connective features evocative but inconclusive for clinical diagnosis of Marfan syndrome (MFS). Targeted (91 genes) NGS was used. Proband genetic variants were investigated in first-degree relatives. Proband carried 5 rare variants in 4 genes: (p.Asn542Ser and p.Lys2460Arg), (p.Val1739Met), (p.Arg1330Gln), and (p.Arg423Trp). The two FBN1 variants were inherited in cis by the mother, showing systemic features evocative of MFS, but with a milder phenotype than that observed in the proband. Careful clinical observation along with the presence of the variants allowed diagnosis of MFS in the proband and in his mother. variant was found in mother and brother, not exhibiting BAV, thus not definitely supporting/excluding association with BAV. Interestingly, the proband, his brother and father, all showing root dilatation, and his sister, with upper range aortic root dimension, were carriers of a variant. might also modulate the vascular phenotype. Our results underline the usefulness of NGS together with family evaluation in diagnosis of patients with monogenic traits and overlapping clinical manifestations due to contribution of the same genes and/or presence of comorbidities determined by different genes.
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http://dx.doi.org/10.1155/2018/8386123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145047PMC
January 2019

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study.

BMC Cancer 2018 May 18;18(1):568. Epub 2018 May 18.

Department of Neuroscience, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy.

Background: Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients.

Methods: We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.

Results: Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol).

Conclusions: Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory.

Trial Registration: CRD42017057740 .
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http://dx.doi.org/10.1186/s12885-018-4478-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960169PMC
May 2018

Transient Neonatal Diabetes Mellitus in a Very Preterm Infant due to ABCC8 Mutation.

AJP Rep 2018 Jan 7;8(1):e39-e42. Epub 2018 Mar 7.

Department of Neuroscience, Psychology, Drug Research and Child Health, Careggi University Hospital of Florence, Florence, Italy.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes occurring within 6 months from birth. NDM can be permanent or transient (TNDM). We report the case of a preterm infant with TNDM due to an ABCC8 mutation identified by next-generation sequencing. The pancreatic adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes. The patient was successfully managed with insulin lispro at a 1:100 dilution, drawn up in an insulin pen injector with a 4-mm needle. The insulin lispro dilution allowed administration of the exact insulin doses, obtaining a good glycemic control and minimizing the burden of injections. At 2 months, corrected age insulin doses were progressively decreased until discontinuation.
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http://dx.doi.org/10.1055/s-0038-1636427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842069PMC
January 2018

SLMSuite: a suite of algorithms for segmenting genomic profiles.

BMC Bioinformatics 2017 Jun 28;18(1):321. Epub 2017 Jun 28.

Department of Experimental and Clinical Medicine, University of Florence, Viale Pieraccini 6, Florence, 50139, Italy.

Background: The identification of copy number variants (CNVs) is essential to study human genetic variation and to understand the genetic basis of mendelian disorders and cancers. At present, genome-wide detection of CNVs can be achieved using microarray or second generation sequencing (SGS) data. Although these technologies are very different, the genomic profiles that they generate are mathematically very similar and consist of noisy signals in which a decrease or increase of consecutive data represent deletions or duplication of DNA. In this framework, the most important step of the analysis consists of segmenting genomic profiles for the identification of the boundaries of genomic regions with increased or decreased signal.

Results: Here we introduce SLMSuite, a collection of algorithms, based on shifting level models (SLM), to segment genomic profiles from array and SGS experiments. The SLM algorithms take as input the log-transformed genomic profiles from SGS or microarray experiments and output segmentation results. We apply our method to the analysis of synthetic genomic profiles and real whole genome sequencing data and we demonstrate that it outperforms the state of the art circular binary segmentation algorithm in terms of sensitivity, specificity and computational speed.

Conclusion: The SLMSuite contains an R library with the segmentation methods and three wrappers that allow to use them in Python, Ruby and C++. SLMSuite is freely available at https://sourceforge.net/projects/slmsuite .
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http://dx.doi.org/10.1186/s12859-017-1734-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490196PMC
June 2017
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