Assuntos
Antineoplásicos , Antivirais , Neoplasias do Ânus , Betapapillomavirus , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Humanos , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/virologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/virologia , Receptores CXCR4/antagonistas & inibidores , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/virologia , Doenças da Imunodeficiência Primária/tratamento farmacológico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/virologia , Verrugas/tratamento farmacológico , Verrugas/genética , Verrugas/virologia , Mutação com Ganho de FunçãoRESUMO
Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.
Assuntos
Agamaglobulinemia , Carcinoma , Infecções por Vírus Epstein-Barr , Linfoma , Infecções por Papillomavirus , Doenças da Imunodeficiência Primária , Verrugas , Humanos , Adulto , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Verrugas/complicações , Verrugas/epidemiologia , Verrugas/diagnóstico , Síndrome , Receptores CXCR4RESUMO
Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and ß-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.
Assuntos
Diabetes Mellitus Tipo 2 , Fator 4 Nuclear de Hepatócito , Regiões Promotoras Genéticas , Ativação Transcricional , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Ativação Transcricional/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Hep G2 , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linhagem CelularRESUMO
Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.
Assuntos
Deficiência de GATA2 , Transtornos Mieloproliferativos , Humanos , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Transtornos Mieloproliferativos/genética , Mutação , Medula Óssea , Mutação em Linhagem Germinativa , Fator de Transcrição GATA2/genéticaRESUMO
Severe congenital neutropenias (SCNs) are rare diseases, and to date about 30 subtypes have been described according to their genetic causes. Standard care aims to prevent infections and limit the risk of leukemic transformation; however, several subtypes may have additional organ dysfunction(s), requiring specialized care. Granulocyte colony-stimulating factor and hematopoietic stem cell transplantation are now the bedrock of standard care. Better understanding of SCN mechanisms now offers the possibility of adapted therapy for some entities. An inhibitor of sodium glucose cotransporter, an antidiabetic drug, may attenuate glycogen storage disease type Ib and glucose-6-phosphatase catalytic subunit 3 neutropenias by clearing 1,5-anhydroglucitol, the precursor of the phosphate ester responsible for these SCNs. Chemokine receptor CXCR4 inhibitors contribute to reversing the leukocyte defect in warts, hypoglobulinemia, infections, and myelokathexis syndrome. All these new approaches use oral drugs, which notably improve quality of life. Additionally, improved research into clonal evolution has highlighted some ways to potentially prevent leukemia, such as stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation.
Assuntos
Doença de Depósito de Glicogênio Tipo I , Neutropenia , Humanos , Qualidade de Vida , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Neutropenia/genética , Neutropenia/terapia , Neutropenia/congênito , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/genética , Fator Estimulador de Colônias de Granulócitos/uso terapêuticoRESUMO
Neutropenia related to ELANE gene mutations predisposes patients to infection and leukemia/myelodysplasia, but little is known about the predisposition to cancer. Among a cohort of 147 patients, we identified four with malignant solid tumors (papillary thyroid cancer, anal squamous cell cancer, papillary renal cell carcinoma, and adrenocortical carcinoma), all aged 25-50 years. Three occurred with cyclic neutropenia, and one occurred with severe chronic neutropenia. Previous radiotherapy was identified as a risk factor in one patient. No genetic predisposition was identified in the three other patients.
Assuntos
Neoplasias , Neutropenia , Humanos , Elastase de Leucócito/genética , Mutação , Neoplasias/complicações , Neutropenia/genética , Neutropenia/patologia , Sistema de RegistrosRESUMO
Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Receptores da Eritropoetina , Trombocitemia Essencial , Alelos , Mutação com Ganho de Função , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Policitemia Vera/genética , Receptores da Eritropoetina/genética , Trombocitemia Essencial/genéticaAssuntos
Síndrome Congênita de Insuficiência da Medula Óssea , Neutropenia , Receptores de Interleucina-8B/genética , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Humanos , Mutação com Perda de Função , Neutropenia/congênito , Neutropenia/diagnóstico , Neutropenia/genéticaRESUMO
The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Cromossomos Humanos Par 14/genética , Hematopoiese Clonal , Duplicação Gênica , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Repressoras/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Suscetibilidade a Doenças , Feminino , Seguimentos , Células Germinativas , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Endopeptidase Clp/genética , Neutropenia/congênito , Células Cultivadas , Endopeptidase Clp/química , Exoma , Feminino , Variação Genética , Heterozigoto , Humanos , Lactente , Masculino , Modelos Moleculares , Mutação , Neutropenia/genéticaRESUMO
INTRODUCTION: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.
Assuntos
Infecções Bacterianas , Neutropenia , Antibioticoprofilaxia/efeitos adversos , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/diagnóstico , Neutropenia/etiologia , Neutropenia/terapiaRESUMO
Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3 ), high lymphocyte count (>3000/mm3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.
Assuntos
Infecções Bacterianas/etiologia , Elastase de Leucócito/análise , Micoses/etiologia , Neutropenia/complicações , Adolescente , Adulto , Infecções Bacterianas/genética , Criança , Seguimentos , França/epidemiologia , Variação Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Elastase de Leucócito/genética , Micoses/genética , Neutropenia/genética , Neutropenia/terapia , Recidiva , Sistema de Registros , Adulto JovemRESUMO
Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.
Assuntos
Mutação , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Ribossomos/genética , Ribossomos/patologia , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/patologia , Adolescente , Adulto , Animais , Fenômenos Biológicos , Células Cultivadas , Criança , Pré-Escolar , Dictyostelium , Drosophila , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Células Germinativas , Humanos , Lactente , Simulação de Dinâmica Molecular , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Proteínas/genética , Proteínas/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Ribossomos/metabolismo , Saccharomyces cerevisiae , Homologia de Sequência de Aminoácidos , Síndrome de Shwachman-Diamond/metabolismo , Adulto JovemRESUMO
Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.
Assuntos
Neoplasias , Neutropenia , Síndrome de Shwachman-Diamond , Feminino , Humanos , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/genética , Neutropenia/epidemiologia , Neutropenia/etiologia , Neutropenia/genética , Sistema de Registros , Síndrome de Shwachman-Diamond/complicaçõesRESUMO
ABCC8 encodes the SUR1 subunit of the ß-cell ATP-sensitive potassium channel whose loss of function causes congenital hyperinsulinism (CHI). Molecular diagnosis is critical for optimal management of CHI patients. Unfortunately, assessing the impact of ABCC8 variants on RNA splicing remains very challenging as this gene is poorly expressed in leukocytes. Here, we performed bioinformatics analysis and cell-based minigene assays to assess the impact on splicing of 13 ABCC8 variants identified in 20 CHI patients. Next, channel properties of SUR1 proteins expected to originate from minigene-detected in-frame splicing defects were analyzed after ectopic expression in COSm6 cells. Out of the analyzed variants, seven induced out-of-frame splicing defects and were therefore classified as recessive pathogenic, whereas two led to skipping of in-frame exons. Channel functional analysis of the latter demonstrated their pathogenicity. Interestingly, the common rs757110 SNP increased exon skipping in our system suggesting that it may act as a disease modifier factor. Our strategy allowed determining the pathogenicity of all selected ABCC8 variants, and CHI-inheritance pattern for 16 out of the 20 patients. This study highlights the value of combining RNA and protein functional approaches in variant interpretation and reveals the minigene splicing assay as a new tool for CHI molecular diagnostics.
Assuntos
Biologia Computacional , Hiperinsulinismo Congênito , Receptores de Sulfonilureias , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Éxons/genética , Humanos , Splicing de RNA/genética , Receptores de Sulfonilureias/genéticaRESUMO
PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.