RESUMO
OBJECTIVES: Progressive familial intrahepatic cholestasis is an expanding group of autosomal recessive intrahepatic cholestatic disorders. Recently, next-generation sequencing allowed identifying new genes responsible for new specific disorders. Two biochemical phenotypes have been identified according to gamma-glutamyltransferase (GGT) activity. Mutations of the myosin 5B gene (MYO5B) are known to cause microvillus inclusion disease. Recently, different mutations in MYO5B gene have been reported in patients with low-GGT cholestasis. METHODS: A multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis. Clinical, biochemical, histological, and treatment data were analyzed in these patients. DNA from peripheral blood was extracted, and all patients were studied by whole exome sequencing followed by Sanger sequencing. RESULTS: Six patients out of 32 had mutations in the MYO5B gene. Of these six patients, the median age at disease onset was 0.8âyears, and the median length of follow-up was 4.2âyears. The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. Two patients also showed intestinal involvement. Transaminases and conjugated bilirubin were moderately increased, serum bile acids elevated, and GGT persistently normal. At anti-Myo5B immunostaining, performed in liver biopsy of two patients, coarse granules were evident within the cytoplasm of hepatocytes while bile salt export pump was normally expressed at the canalicular membrane. Six variants in homozygosity or compound heterozygosity in the MYO5B gene were identified, and three of them have never been described before. All nucleotide alterations were located on the myosin motor domain except one missense variant found in the isoleucine-glutamine calmodulin-binding motif. CONCLUSIONS: We identified causative mutations in MYO5B in 18.7% of a selected cohort of patients with intrahepatic cholestasis confirming a relevant role for the MYO5B gene in low-GGT cholestasis.
Assuntos
Colestase Intra-Hepática , Colestase , Miosina Tipo V , Colestase/genética , Colestase Intra-Hepática/diagnóstico , Humanos , Mutação , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Miosinas/genética , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , gama-Glutamiltransferase/genéticaRESUMO
MED13-related disorder is a new neurodevelopmental disorder recently described in literature, which belongs to the group of CDK8-kinase module genes-associated conditions. It is characterized by variable intellectual disability and/or developmental delays, especially in language. Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), eye or vision problems, hypotonia, mild congenital hearth abnormalities and dysmorphisms have been described among individuals with MED13 mutations. We report the case of a 13-year-old girl who received a previous clinical diagnosis of Kabuki syndrome (KS) without mutations in classic KS genes. After a whole exome sequencing (WES) analysis a de novo missense mutation in MED13 (c.C979T; p.Pro327Ser) was found. This variant has been once described in literature as accountable for a novel neurodevelopmental disorder. The aim of this report is to improve clinical delineation of MED13-related condition and to explore differences and similarities between KS spectrum and MED13-related disorders.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Predisposição Genética para Doença , Doenças Hematológicas/genética , Complexo Mediador/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Quinase 8 Dependente de Ciclina/genética , Face/patologia , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/patologia , Humanos , Mutação/genética , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/patologiaRESUMO
Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.
Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Inflamação/genética , Receptores Notch/genética , Animais , Síndrome de Behçet/genética , Síndrome de Behçet/patologia , Diferenciação Celular/genética , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/patologia , Hidradenite Supurativa/genética , Hidradenite Supurativa/patologia , Humanos , Inflamação/patologia , Mutação/genética , Transdução de Sinais/genéticaRESUMO
Most of primary immunodeficiencies with hypogammaglobulinemia are associated with reduced memory B cells. T cell development may be interesting as well, but increased recent thymic emigrants are rarely reported in these patients. We report the case of a family (mother and her two sons) diagnosed with common variable immunodeficiency 10 due to a mutation in the NFKB2 gene. Laboratory findings showed that all three patients presented hypogammaglobulinemia, reduced memory B cells and elevated naïve T lymphocytes and recent thymic emigrants. This feature, in the absence of glucocorticoid deficiency, may suggest a primary thymic dysfunction. Interestingly, the mother presented the worst immune phenotype, as regards both antibody production and NK function, indicating that immune function may deteriorate in the course of time. We conclude that close monitoring of immune functions may widen the knowledge on the CVID10 and improve the patients' care.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Subunidade p52 de NF-kappa B/genética , Linfócitos T/imunologia , Adulto , Linfócitos B/imunologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/genética , Feminino , Humanos , Imunoglobulinas/sangue , Masculino , MutaçãoRESUMO
A severe course of infectious mononucleosis should always lead up to the suspicion of a primary immunodeficiency. We describe the case of a boy with severe mononucleosis accompanied by the development of hemophagocytic lymphohistiocytosis and lymphoma. By whole exome sequencing, we identified a mutation of uncertain significance in CTPS2, a gene closely related to CTPS1, which is involved in a primary immune deficiency with susceptibility to herpesviruses. We discuss the challenge of a correct interpretation of data from whole exome sequencing, questioning whether the CTPS2 variant found in our patient is just an incidental finding or a mutation with variable penetrance.
Assuntos
Exoma , Herpesvirus Humano 4/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mononucleose Infecciosa , Linfoma , Mutação , Adolescente , Humanos , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/virologia , Linfoma/genética , Linfoma/virologia , MasculinoRESUMO
Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The development of MPM is frequently linked to inhalation of asbestos fibers. A genetic component of susceptibility to this disease is suggested by the observation that some individuals develop MPM following lower doses of asbestos exposure, whereas others exposed to higher quantities do not seem to be affected. This hypothesis is supported also by frequent reports of MPM familial clustering. Despite the widely recognized role of iron (Fe) in cellular asbestos-induced pulmonary toxicity, the role of the related gene polymorphisms in the etiology of MPM has apparently not been evaluated. Eighty-six single-nucleotide polymorphisms (SNPs) of 10 Fe-metabolism genes were examined by exploiting formalin-fixed paraffin-embedded postmortem samples from 77 patients who died due to MPM (designated AEM) and compared with 48 who were exposed to asbestos but from died in old age of cause other than asbestos (designated AENM). All subjects showed objective signs of asbestos exposure. Three SNPs, localized in the ferritin heavy polypeptide, transferrin, and hephaestin genes, whose frequencies were distributed differently in AEM and AENM populations, were identified. For ferritin and transferrin the C/C and the G/G genotypes, respectively, representing intronic polymorphisms, were significantly associated with protection against MPM and need to be considered as possible genetic markers of protection. Similarly, the C/C hephaestin SNP, a missense variation of this multicopper ferroxidase encoding gene, may be related, also functionally, with protection against MPM. In conclusion, it is proposed that three Fe metabolism-associated genes, significantly associated with protection against development of MPM, may serve as protective markers for this aggressive tumor.
Assuntos
Amianto/toxicidade , Autopsia , Ferro/metabolismo , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Ferritinas/genética , Frequência do Gene , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Masculino , Proteínas de Membrana/genética , Mesotelioma/induzido quimicamente , Mesotelioma/genética , Mesotelioma Maligno , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oxirredutases , Polimorfismo de Nucleotídeo Único , Transferrina/genética , Adulto JovemRESUMO
The pathological role of mutations that affect not conserved splicing regulatory sequences can be difficult to determine. In a patient with Fanconi anemia, we identified two unpredictable splicing mutations that act on either sides of FANCA exon 8. In patients-derived cells and in minigene splicing assay, we showed that both an apparently benign intronic c.710-5T>C transition and the nonsense c.790C>T substitution induce almost complete exon 8 skipping. Site-directed mutagenesis experiments indicated that the c.710-5T>C transition affects a polypyrimidine tract where most of the thymidines cannot be compensated by cytidines. The c.790C>T mutation located in position -3 relative to the donor site induce exon 8 skipping in an NMD-independent manner and complementation experiments with modified U1 snRNAs showed that U1 snRNP is only partially involved in the splicing defect. Our results highlight the importance of performing splicing functional assay for correct identification of disease-causing mechanism of genomic variants and provide mechanistic insights on how these two FANCA mutations affect exon 8 definition.
Assuntos
Códon sem Sentido , Éxons , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Sítios de Splice de RNA/genética , Splicing de RNA , Sequência de Bases , Linhagem Celular Tumoral , Células HeLa , Humanos , Íntrons , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida/métodos , Ribonucleoproteínas Nucleares PequenasRESUMO
BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT). CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation. CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Inflamatórias Intestinais/etiologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/diagnóstico , Idade de Início , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Doenças Inflamatórias Intestinais/terapia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia , Masculino , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
The knowledge of the human genome is in continuous progression: a large number of databases have been developed to make meaningful connections among worldwide scientific discoveries. This paper reviews bioinformatics resources and database tools specialized in disseminating information regarding genetic disorders. The databases described are useful for managing sample sequences, gene expression and post-transcriptional regulation. In relation to data sets available from genome-wide association studies, we describe databases that could be the starting point for developing studies in the field of complex diseases, particularly those in which the causal genes are difficult to identify.
Assuntos
Bases de Dados Genéticas , Doenças Genéticas Inatas/genética , Genoma Humano , Biologia Computacional , Genômica , HumanosRESUMO
Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease.
Assuntos
Colite Ulcerativa/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Proteína Adaptadora de Sinalização NOD2/genética , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Criança , Colite Ulcerativa/epidemiologia , Doença de Crohn/genética , Análise Mutacional de DNA , Genótipo , Humanos , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/genética , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Homologia de Sequência de AminoácidosRESUMO
Curcumin belongs to the family of natural compounds collectively called curcuminoids and it possesses remarkable beneficial anti-oxidant, anti-inflammatory, anti-cancer, and neuroprotective properties. Moreover it is commonly assumed that curcumin has also been suggested as a remedy for digestive diseases such as inflammatory bowel diseases (IBD), a chronic immune disorder affecting the gastrointestinal tract and that can be divided in two major subgroups: Crohn's disease (CD) and Ulcerative Colitis (UC), depending mainly on the intestine tract affected by the inflammatory events. The chronic and intermittent nature of IBD imposes, where applicable, long-term treatments conducted in most of the cases combining different types of drugs. In more severe cases and where there has been no good response to the drugs, a surgery therapy is carried out. Currently, IBD-pharmacological treatments are generally not curative and often present serious side effects; for this reason, being known the relationship between nutrition and IBD, it is worthy of interesting the study and the development of new dietary strategy. The curcumin principal mechanism is the suppression of IBD inflammatory compounds (NF-κB) modulating immune response. This review summarizes literature data of curcumin as anti-inflammatory and anti-oxidant in IBD, trying to understand the different effects in CD e UC.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Química Farmacêutica , Ensaios Clínicos como Assunto , Curcumina/análogos & derivados , Curcumina/farmacologia , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/etiologia , Terapia de Alvo Molecular , Nanotecnologia , Resultado do TratamentoRESUMO
Primary complement system (C) deficiencies are rare but notably associated with an increased risk of infections, autoimmunity, or immune disorders. Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of Neisseria meningitidis infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination. In this paper, we performed a systematic review about clinical and genetic patterns of C7 deficiency starting from the case of a ten-year old boy infected by Neisseria meningitidis B and with clinical presentation suggestive of reduced C activity. Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum. Sanger sequencing of genomic DNA extracted from peripheral blood of the patient allowed the identification of two pathogenetic variants in the C7 gene: the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3'UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA; thus, only the allele containing the missense mutation was expressed, making the proband a functional hemizygote for the expression of the mutated C7 allele.
Assuntos
Autoimunidade , Bioensaio , Masculino , Humanos , Criança , Regiões 3' não Traduzidas , AlelosRESUMO
BACKGROUND: A potential anti-inflammatory effect of clodronate--an aminobisphosphonate--was described to antagonize the pro-inflammatory effects of the block in the mevalonate pathway, the main feature of a rare auto-inflammatory disease called mevalonate kinase deficiency (MKD). OBJECTIVE: In this study we evaluated the potential anti-inflammatory effect of clodronate in MKD--a still orphan drug pediatric disease. METHODS: We studied some biological parameters, nitric oxide production using Griess reagents and programmed cell death by flow cytometry, as common inflammatory parameters in MKD, in the presence of different doses of clodronate (1, 10 and 100 µM). RESULTS: In our cellular model and in monocytes from patients with MKD, clodronate induced an increase in programed cell death and nitric oxide production in comparison with non-treated cells. CONCLUSION: Our findings suggest that clodronate does not have an anti-inflammatory effect as previously reported but that it increases the epiphenomena of this pediatric disease.
Assuntos
Anti-Inflamatórios/farmacologia , Ácido Clodrônico/farmacologia , Deficiência de Mevalonato Quinase , Modelos Biológicos , Monócitos/efeitos dos fármacos , Adolescente , Adulto , Alendronato , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Criança , Feminino , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Masculino , Camundongos , Óxido Nítrico/metabolismo , Adulto JovemRESUMO
Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 and TBX4, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in PITX1 and TBX4 in Italian patients with idiopathic clubfoot. PITX1 and TBX4 genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in TBX4, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on PITX1 and TBX4. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same TBX4-PITX1 axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors.
Assuntos
Pé Torto Equinovaro , Criança , Humanos , Pé Torto Equinovaro/genética , Variações do Número de Cópias de DNA/genética , Mutação , Proteínas com Domínio T/genéticaRESUMO
Nonsyndromic cleft lip with or without cleft palate (CL/P) affects approximately 1 in 1,000 births. Genetic studies have provided evidence for the role of several genes and candidate loci in clefting; however, conflicting results have frequently been obtained and much have to be done to unravel the complex genetics of CL/P. In the present investigation we have focused on the candidate region in 6p23, a region that have been found linked to CL/P in several investigations, in the attempt to find out the susceptibility gene provisionally named OFC1. Gene expression experiments in mice embryo of positional candidate genes revealed that JARID2 was highly and specifically expressed in epithelial cells in merging palatal shelves. A family-based linkage disequilibrium study confirmed the pivotal role of JARID2 in orofacial development and strongly supports a role for this gene in CL/P etiology (multiallelic haplotype test P=6 x 10(-5)). Understanding the molecular role of JARID2 within facial development may offer additional information to further unravel the complex genetics of CL/P.
Assuntos
Fenda Labial/genética , Fissura Palatina/complicações , Expressão Gênica , Proteínas do Tecido Nervoso/genética , Animais , Fenda Labial/complicações , Análise Mutacional de DNA , Saúde da Família , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Haplótipos , Humanos , Hibridização In Situ , Desequilíbrio de Ligação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Palato/embriologia , Palato/metabolismo , Complexo Repressor Polycomb 2 , Polimorfismo de Nucleotídeo Único , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO). METHODS: The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF < 2%), coding variants detected were considered. Clinical evaluation of patients with rare variants and those without was performed. Fisher's exact test was used to compare categorical and ordinal data, and Student's t-test was used to analyze continuous data. RESULTS: Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome. CONCLUSION: Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.
Assuntos
Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Osteomielite , Remodelação Óssea/genética , Criança , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Itália/epidemiologia , Masculino , Osteomielite/diagnóstico , Osteomielite/epidemiologia , Osteomielite/genética , Polimorfismo Genético , PrevalênciaRESUMO
BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected. RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.