Publications by authors named "Sımona Baldassari"

Immune dysregulation in Inborn Errors of Immunity (IEI) shows a broad phenotype, including autoimmune disorders, benign lymphoproliferation, and malignancies, driven by an increasing number of implicated genes. Recent findings suggest that childhood cancer survivors (CCSs) may exhibit immunological abnormalities potentially linked to an underlying IEI, along with a well-known increased risk of subsequent malignancies due to prior cancer treatments. We describe a patient with two composite heterozygous pathogenic variants in the interleukin-2-inducible T-cell kinase () gene and a history of multiple tumors, including recurrent Epstein-Barr virus (EBV)-related nodular sclerosis and Hodgkin's lymphoma (NSHL), associated with unresponsive multiple hand warts, immune thrombocytopenia, and an impaired immunological profile (CD4+ lymphocytopenia, memory B-cell deficiency, reduction in regulatory T-cells, and B-cell- and T-cell-activated profiles).

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The human gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic variants were reported with progressive neurodegeneration, consequences of monoallelic variants have not been elucidated.

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The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects.

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ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various tissues and its role is fundamental for the correct development of the nervous system. The best-known clinical picture associated with ZEB2 mutations is Mowat-Wilson syndrome, caused mostly by haploinsufficiency and characterized by possible multi-organ malformations, dysmorphic features, intellectual disability, and epilepsy.

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Sotos syndrome (SoS) is a neurodevelopmental disorder that results from NSD1 mutations that cause haploinsufficiency of NSD1. Here, we generated an induced pluripotent stem cell (iPSC) line from fibroblasts of a SoS patient carrying the pathogenic variant (c.1633delA).

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WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities.

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Article Synopsis
  • Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is crucial for chloride channels, and defects like the G542X mutation lead to cystic fibrosis by stopping protein production.
  • A new induced pluripotent stem cell (iPSC) line, IGGi002A, was created from nasal cells with the G542X mutation and shows normal characteristics for further research.
  • This iPSC line can help in modeling cystic fibrosis, allowing for better understanding of the disease and potential personalized treatment options through techniques like genome editing.
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Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events.

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Sotos syndrome (SoS) is a neurodevelopmental disorder caused by haploinsufficiency of the NSD1 gene located on chromosome 5 region q35.3. In order to understand the pathogenesis of Sotos syndrome and in view of future therapeutic approaches for its efficient treatment, we generated two human induced pluripotent stem cells (iPSCs) lines from one SoS patient carrying a 5q35 microdeletion.

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Segmental overgrowth syndromes include a group of clinical entities, all characterized by the abundant proliferation of tissues or organs in association with vascular abnormalities. These syndromes show a wide spectrum of severity ranging from limited involvement of only small areas of the body to complex cases with impressive distortions of multiple tissues and organs. It is now clear that somatic mutations in genes of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (in brief "mTOR pathway") are responsible for such entities.

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Article Synopsis
  • Human-induced pluripotent stem cells (hiPSCs) are valuable for modeling neurological diseases but traditional methods using animal-derived substances present challenges for clinical applications.
  • This study focuses on optimizing a feeder-free protocol to generate functional glutamatergic neurons from hiPSCs, using neurotrophins and a Geltrex-coated substrate for improved differentiation.
  • Results confirmed the effectiveness of this new approach through various analyses, demonstrating that the hiPSC-derived neurons exhibit essential features of mature neurons, which could enhance future drug discovery efforts.
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Background: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive.

Methods: We report five families carrying biallelic variants in PEX13.

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  • Cystic Fibrosis (CF) is a genetic disorder caused by mutations like F508del that prevent the CFTR protein from reaching the cell membrane, impacting lung function in many newborns.
  • Researchers used advanced methods, such as mass spectrometry and bioinformatics, to analyze protein changes in a CF cell model after treatment with VX-809, a drug that helps CFTR trafficking.
  • Results indicated that while overall protein expression didn't change significantly, there were notable shifts in the localization of mitochondrial and peroxisomal proteins, suggesting VX-809 may promote healthier cell characteristics beyond just improving CFTR transport.
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  • The study investigates the neurodevelopmental outcomes in patients with developmental and epileptic encephalopathy (DEE), focusing on the relationship between neurodevelopment and epilepsy.
  • Researchers analyzed clinical data from 48 patients and found that seizure onset age influences developmental progress, with later onset linked to better outcomes, while seizure duration and remission age did not significantly affect development.
  • The results highlight two main disease trajectories—either early seizure remission or drug-resistant epilepsy—suggesting a wide range of neurodevelopmental impacts and the need for more focused future research on DEE.
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Article Synopsis
  • - WOREE syndrome is a rare neurodevelopmental disorder characterized by severe drug-resistant epilepsy and developmental delays, often leading to significant disability or death in early childhood.
  • - A case study reports a boy diagnosed with WOREE syndrome through various genetic tests, revealing a pathogenic variant and a large deletion in his genetic material.
  • - The study emphasizes the importance of genetic testing for accurate diagnosis and potential early interventions, while also noting that specific testing methods may have limitations that necessitate additional investigations.
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Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth.

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  • Wieacker-Wolff syndrome (WWS) is an X-linked genetic disorder causing severe developmental and muscular issues, linked to mutations affecting brain development.
  • A Sicilian family case study identified a specific hemizygous variant in the associated gene, leading to symptoms like short stature, neurological delays, and recurrent hypoglycemia in a boy.
  • Muscle biopsies revealed unique neuromuscular junction abnormalities, highlighting the need for further understanding of WWS's wide-ranging effects on neurodevelopment and muscle function.
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  • Currarino syndrome (CS) is a rare genetic disorder marked by anorectal malformation, sacro-coccygeal bone defects, and presacral masses, often seen more in females who may also face gynecologic and urinary issues.
  • The condition is linked to mutations in the MNX1 gene on chromosome 7q36, with the majority of familial cases showing heterozygous loss-of-function mutations, while about 30% of sporadic cases do.
  • A unique case is discussed where a woman with CS has a mosaic mutation in the MNX1 gene, highlighting that such mutations could also explain the lower detection rates in sporadic cases through mechanisms like somatic mosaicism.
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Objective: To describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy.

Methods: We investigated by Sanger and targeted resequencing the gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened.

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Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1.

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Article Synopsis
  • Neurodevelopmental disorders (NDDs) affect central nervous system development, leading to issues like motor function impairments and learning difficulties, often accompanied by conditions like epilepsy.
  • Advances in DNA sequencing have uncovered genetic factors in many NDDs, but studying these requires patient-derived brain tissues, which are difficult to access.
  • Innovations in stem cell technology and genome editing have enabled the creation of 3D cerebral organoids, providing new ways to model human brain development and investigate disorders such as autism and epileptic encephalopathies.
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Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in , the gene encoding the pore-forming α subunit of P/Q-type voltage-gated Ca channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients.

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Mutations in the gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous mutation leading to a premature stop codon.

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Purpose: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations.

Methods: A total of 84 subjects with different MCD were enrolled.

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