Characterization of a novel FLI1 mutation in a family with thrombocytopenia and other congenital malformations.

Not available.

A computational study of the fold and stability of cytochrome c with implications for disease.

Cytochrome c (Cyt-c), encoded by the CYCS gene, is crucial for electron transport, peroxidase activity, and apoptosis. Mutations in CYCS cause thrombocytopenia 4 (THC4), a disorder with low platelet counts. We have, for instance, recently described six Italian families with five different heterozygous missense CYCS variants.

A novel de novo GFAP variant causes a juvenile-onset Alexander disease with bilateral vocal cord paralysis.

Alexander disease (AxD), an autosomal dominant leukodystrophy, is caused by mutations in the GFAP, the gene encoding glial fibrillary acidic protein (GFAP). The disease, classified by age of onset into infantile, juvenile, and adult forms, is characterized by white matter degeneration and astrocytic inclusions called Rosenthal fibers. A patient underwent clinical, radiological, and molecular analyses to confirm a suspected diagnosis of AxD.

Functional Testing of ETV6 Variants: Is the Evaluation of Their Intracellular Localization Sufficient in Assessing Pathogenicity?

Background/objectives: ETV6-related thrombocytopenia (ETV6-RT) is a rare autosomal dominant disorder characterized by mild thrombocytopenia since birth and an increased predisposition to hematologic malignancies. ETV6 functions as a transcriptional repressor, and its pathogenic variants, predominantly within the ETS domain, disrupt nuclear localization and transcriptional activity. In individuals with congenital thrombocytopenia, we identified two missense variants: c.

Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6.

Mutations in the genes , , and cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5'UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia.

Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene.

Thrombocytopenia 4 (THC4) is an autosomal-dominant thrombocytopenia caused by mutations in CYCS, the gene encoding cytochrome c (CYCS), a small haeme protein essential for electron transport in mitochondria and cell apoptosis. THC4 is considered an extremely rare condition since only a few patients have been reported so far. These subjects presented mild thrombocytopenia and no or mild bleeding tendency.

Identification of a robust DNA methylation signature for Fanconi anemia.

Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is caused by inactivating predominantly biallelic mutations involving >20 genes encoding proteins with roles in the FA/BRCA DNA repair pathway. Molecular diagnosis of FA is challenging due to the wide spectrum of the contributing gene mutations and structural rearrangements.

Phenotype reversion as "natural gene therapy" in Fanconi anemia by a gene conversion event.

Somatic mosaicism appears as a recurrent phenomenon among patients suffering from Fanconi anemia (FA), but its direct prognostic significance mostly remains an open question. The clinical picture of FA mosaic subjects could indeed vary from just mild features to severe hematologic failure. Here, we illustrate the case of a proband whose FA familiarity, modest signs (absence of hematological anomalies and fertility issues), and chromosome fragility test transition to negative overtime were suggestive of somatic mosaicism.

A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure.

MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1.

A self-repair history: compensatory effect of a variant on the c.2778+83C>G splicing mutation.

Fanconi anemia (FA) is a genome instability condition that drives somatic mosaicism in up to 25% of all patients, a phenomenon now acknowledged as a good prognostic factor. Herein, we describe the case of P1, a FA proband carrying a splicing variant, molecularly compensated by a insertion. Targeted next-generation sequencing on P1's peripheral blood DNA detected the known c.

Exome sequencing in 116 patients with inherited thrombocytopenia that remained of unknown origin after systematic phenotype-driven diagnostic workup.

Inherited thrombocytopenias (IT) are genetic diseases characterized by low platelet count, sometimes associated with congenital defects or a predisposition to develop additional conditions. Next-generation sequencing has substantially improved our knowledge of IT, with more than 40 genes identified so far, but obtaining a molecular diagnosis remains a challenge especially for patients with non-syndromic forms, having no clinical or functional phenotypes that raise suspicion about specific genes. We performed exome sequencing (ES) in a cohort of 116 IT patients (89 families), still undiagnosed after a previously validated phenotype-driven diagnostic algorithm including a targeted analysis of suspected genes.

"CHildren with Inherited Platelet disorders Surveillance" (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: Inherited thrombocytopenias (ITs) are rare congenital bleeding disorders characterized by different clinical expression and variable prognosis. ITs are poorly known by clinicians and often misdiagnosed with most common forms of thrombocytopenia.

Material And Methods: "CHildren with Inherited Platelet disorders Surveillance" study (CHIPS) is a retrospective - prospective observational cohort study conducted between January 2003 and January 2022 in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP).

Defective binding of ETS1 and STAT4 due to a mutation in the promoter region of as a novel mechanism of congenital amegakaryocytic thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a recessive disorder characterized by severe reduction of megakaryocytes and platelets at birth, which evolves toward bone marrow aplasia in childhood. CAMT is mostly caused by mutations in MPL (CAMT-MPL), the gene encoding the receptor of thrombopoietin (THPO), a crucial cytokine regulating hematopoiesis. CAMT can be also due to mutations affecting the THPO coding region (CAMT-THPO).

A Novel Mutation in Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly.

Bernard-Soulier syndrome (BSS) is an autosomal-recessive bleeding disorder caused by biallelic variants in the , , and genes encoding the subunits GPIbα, GPIbβ, and GPIX of the GPIb-IX complex. Pathogenic variants usually affect the extracellular or transmembrane domains of the receptor subunits. We investigated a family with BSS caused by the homozygous c.

Dysregulation of oncogenic factors by GFI1B p32: investigation of a novel germline mutation.

GFI1B is a transcription factor essential for the regulation of erythropoiesis and megakaryopoiesis, and pathogenic variants have been associated with thrombocytopenia and bleeding. Analysing thrombocytopenic families by whole exome sequencing, we identified a novel GFI1B variant (c.648+5G>A), which causes exon 9 skipping and overexpression of a shorter p32 isoform.

Genomic integrity and mitochondrial metabolism defects in Warsaw syndrome cells: a comparison with Fanconi anemia.

Warsaw breakage syndrome (WABS), is caused by biallelic mutations of DDX11, a gene coding a DNA helicase. We have recently reported two affected sisters, compound heterozygous for a missense (p.Leu836Pro) and a frameshift (p.

Two further patients with Warsaw breakage syndrome. Is a mild phenotype possible?

Background: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms.

Methods: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients.

Loss-of-function mutations in cause a new form of inherited thrombocytopenia.

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count that may result in bleeding tendency. Despite progress being made in defining the genetic causes of ITs, nearly 50% of patients with familial thrombocytopenia are affected with forms of unknown origin. Here, through exome sequencing of 2 siblings with autosomal-recessive thrombocytopenia, we identified biallelic loss-of-function variants in This gene encodes for a receptor-like PTP, PTPRJ (or CD148), which is expressed abundantly in platelets and megakaryocytes.