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RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Adulto , Humanos , Grupos Minoritarios , Israel/epidemiología , Marcadores Genéticos , Estudios Transversales , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/diagnóstico , Poblaciones Minoritarias, Vulnerables y Desiguales en SaludRESUMEN
BACKGROUND: The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. METHODS: Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. RESULTS: The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. CONCLUSIONS: The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.
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Etnicidad , Genómica , Humanos , Etnicidad/genética , Árabes , Pruebas GenéticasRESUMEN
INTRODUCTION: Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members. METHODS: Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample. RESULTS: Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample. CONCLUSION: Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.
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Displasia Ventricular Derecha Arritmogénica , Cardiomiopatías , Taquicardia Ventricular , Humanos , Conexina 43/genética , Conexina 43/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Cardiomiopatías/complicaciones , Mutación/genética , Arritmias Cardíacas/complicaciones , Taquicardia Ventricular/genética , Taquicardia Ventricular/complicaciones , Miocitos Cardíacos/metabolismo , Desmogleína 2/genética , Desmogleína 2/metabolismoRESUMEN
BACKGROUND: SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α). METHODS: We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject. RESULTS: We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression. CONCLUSION: Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.
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Tel Hashomer camptodactyly syndrome is a long-known entity characterized by camptodactyly with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases. Currently, the genetic basis for this disorder is unknown, thus there is a possibility that this clinical presentation may be contained within another genetic diagnosis. Here, we present a multiplex family with a previous clinical diagnosis of Tel Hashomer camptodactyly syndrome. Whole exome sequencing and pedigree-based analysis revealed a novel hemizygous truncating variant c.269_270dup (p.Phe91Alafs*34) in the FGD1 gene (NM_004463.3) in all three symptomatic patients, congruous with a diagnosis of Aarskog-Scott syndrome. Our report adds to the limited data on Aarskog-Scott syndrome, and emphasizes the importance of unbiased comprehensive molecular testing toward establishing a diagnosis for genetic syndromes with unknown genetic basis.
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Enanismo/diagnóstico , Cara/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Predisposición Genética a la Enfermedad , Genitales Masculinos/anomalías , Factores de Intercambio de Guanina Nucleótido/genética , Deformidades Congénitas de la Mano/diagnóstico , Cardiopatías Congénitas/diagnóstico , Defectos del Tabique Interatrial/diagnóstico , Hirsutismo/diagnóstico , Enfermedades Musculares/diagnóstico , Diagnóstico Diferencial , Enanismo/genética , Enanismo/patología , Cara/patología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Genitales Masculinos/patología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/genética , Hirsutismo/genética , Humanos , Deformidades Congénitas de las Extremidades , Masculino , Enfermedades Musculares/genética , Linaje , Secuenciación del ExomaRESUMEN
BACKGROUND: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes. OBJECTIVE: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes. METHODS: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues. RESULTS: Both patients were found homozygous for CHEK2 c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in CHEK2 (c.1283C>T; p.Ser428Phe). CONCLUSIONS: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.
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Quinasa de Punto de Control 2/genética , Predisposición Genética a la Enfermedad , Neoplasias/genética , Translocación Genética/genética , Adulto , Anciano , Quinasa de Punto de Control 2/ultraestructura , Femenino , Homocigoto , Humanos , Cariotipo , Masculino , Persona de Mediana Edad , Neoplasias/patología , Linaje , Conformación ProteicaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Ensamble y Desensamble de Cromatina/genética , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Anomalías Musculoesqueléticas/genética , Mutación Missense/genética , Fenotipo , Síndrome , Factores de Transcripción/genéticaRESUMEN
Agenesis of the corpus callosum (ACC) is a common prenatally-detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4-year-old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss-of-function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss-of-function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination.
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Agenesia del Cuerpo Calloso/genética , Receptor DCC/genética , Trastornos del Movimiento/genética , Malformaciones del Sistema Nervioso/genética , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Agenesia del Cuerpo Calloso/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Niño , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/fisiopatología , Femenino , Asesoramiento Genético , Heterocigoto , Humanos , Masculino , Trastornos del Movimiento/diagnóstico por imagen , Trastornos del Movimiento/fisiopatología , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/fisiopatología , Penetrancia , Embarazo , Diagnóstico PrenatalRESUMEN
Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.
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Artrogriposis/genética , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Glicina/líquido cefalorraquídeo , Hiperglicinemia no Cetósica/genética , Animales , Artrogriposis/diagnóstico , Preescolar , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Glicina/sangre , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Humanos , Hiperglicinemia no Cetósica/diagnóstico , Lactante , Recién Nacido , Masculino , Ratones , Ratones Noqueados , LinajeRESUMEN
PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.
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Colitis/diagnóstico , Colitis/etiología , Enteritis/diagnóstico , Enteritis/etiología , Eosinofilia/diagnóstico , Eosinofilia/etiología , Gastritis/diagnóstico , Gastritis/etiología , Homocigoto , Proteínas de Microfilamentos/genética , Mutación , Fenotipo , Edad de Inicio , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Proteínas de Microfilamentos/química , Modelos Moleculares , Relación Estructura-Actividad , Secuenciación del ExomaRESUMEN
Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.
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Acidosis Láctica/genética , Cardiomiopatías/genética , Errores Innatos del Metabolismo/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Factor Tu de Elongación Peptídica/genética , Acidosis Láctica/fisiopatología , Secuencia de Aminoácidos/genética , Cardiomiopatías/fisiopatología , Consanguinidad , ADN Mitocondrial/genética , Femenino , Homocigoto , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/fisiopatología , Enfermedades Mitocondriales/fisiopatología , Mutación , Fosforilación Oxidativa , Secuenciación del ExomaRESUMEN
OBJECTIVES: Loss of the complement inhibitor CD55 leads to a syndrome of early-onset protein-losing enteropathy (PLE), associated with intestinal lymphangiectasia and susceptibility to large-vein thrombosis. The in vitro and short-term treatment benefits of eculizumab (C5-inhibitor) therapy for CD55-deficiency have been previously demonstrated. Here we present the 18-months treatment outcomes for 3 CD55-deficiency patients with sustained therapeutic response. METHODS: Three CD55-deficiency patients received off-label eculizumab treatment. Clinical and laboratory treatment outcomes included frequency and consistency of bowl movements, weight, patient/parent reports of overall well-being, and serum albumin and total protein levels. Membrane attack complex deposition on leukocytes was tested by flow cytometry, before and during eculizumab treatment. RESULTS: Marked clinical improvement was noted in all 3 patients with resolution of PLE manifestations, that is, diarrhea, edema, malabsorption, overall well-being, growth, and quality of life. In correlation with the clinical observations, we observed progress in all laboratory outcome parameters, including increase in albumin and total protein levels, and up to 80% reduction in membrane attack complex deposition on leukocytes (P < 0.001). The progress persisted over 18 months of treatment without any severe adverse events. CONCLUSIONS: CD55-deficiency patients present with early-onset diarrhea, edema, severe hypoalbuminemia, abdominal pain, and malnutrition. Targeted therapy with the terminal complement inhibitor eculizumab has positive clinical and laboratory outcomes in PLE related to CD55 loss-of-function mutations, previously a life-threatening condition. Our results demonstrate the potential of genetic diagnosis to guide tailored treatment, and underscore the significant role of the complement system in the intestine.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígenos CD55/deficiencia , Inactivadores del Complemento/administración & dosificación , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Adulto , Niño , Preescolar , Ensayos de Uso Compasivo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Linfangiectasia Intestinal/complicaciones , Linfangiectasia Intestinal/patología , Uso Fuera de lo Indicado , Estudios Prospectivos , Enteropatías Perdedoras de Proteínas/etiología , Calidad de Vida , Inducción de RemisiónRESUMEN
BACKGROUND: Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency. OBJECTIVE: To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years. METHODS: Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function. RESULTS: We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein's transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected. CONCLUSIONS: Biallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP's importance in EC barrier function in the gut.
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Proteínas Portadoras/genética , Estudios de Asociación Genética , Homocigoto , Proteínas de la Membrana/genética , Mutación Missense , Fenotipo , Enteropatías Perdedoras de Proteínas/diagnóstico , Enteropatías Perdedoras de Proteínas/genética , Adulto , Sustitución de Aminoácidos , Biomarcadores , Biopsia , Proteínas Portadoras/química , Biología Computacional/métodos , Consanguinidad , Femenino , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana/química , Modelos Moleculares , Linaje , Conformación Proteica , Enteropatías Perdedoras de Proteínas/metabolismo , Relación Estructura-Actividad , Adulto JovenAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD55/genética , Mutación del Sistema de Lectura , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Enteropatías Perdedoras de Proteínas/genética , Niño , Preescolar , Ensayos de Uso Compasivo , Activación de Complemento , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Diarrea/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Análisis de Secuencia de ADN , Albúmina Sérica/metabolismo , Adulto JovenRESUMEN
Increasingly, next-generation sequencing (NGS) is becoming an invaluable tool in the diagnosis of unexplained acute neurological disorders, such as acute encephalopathy/encephalitis. Here, we describe a brief series of pediatric patients who presented at the pediatric intensive care unit with severe acute encephalopathy, initially suspected as infectious or inflammatory but subsequently diagnosed with a monogenic disorder. Rapid exome sequencing was performed during the initial hospitalization of three unrelated patients, and results were delivered within 7-21 days. All patients were previously healthy, 1.5-3 years old, of Muslim Arab descent, with consanguineous parents. One patient presenting with acute necrotizing encephalopathy (ANEC). Her sister presented with ANEC one year prior. Exome sequencing was diagnostic in all three patients. All were homozygous for pathogenic and likely-pathogenic variants associated with recessive disorders; MOCS2, NDUFS8 and DBR1. Surprisingly, the initial workup was not suggestive of the final diagnosis. This case series demonstrates that the use of rapid exome sequencing is shifting the paradigm of diagnostics even in critical care situations and should be considered early on in children with acute encephalopathy. A timely diagnosis can direct initial treatment as well as inform decisions regarding long-term care.
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Encefalopatías , Enfermedades del Sistema Nervioso , Femenino , Humanos , Niño , Lactante , Preescolar , Secuenciación del Exoma , Exoma/genética , Homocigoto , Encefalopatías/diagnóstico , Encefalopatías/genéticaRESUMEN
BACKGROUND: Autosomal recessive conditions are common in consanguineous populations. Since consanguinity is common in the Israeli Arab population, we evaluated the rate of MUTYH polyposis (MAP) among polyposis patients in this population and studied Pathogenic Variants (PVs) spectrum. METHODS: We reviewed health records of all Arab and Druze polyposis patients referred for counseling during 2013-2020 who fulfilled the Israeli Genetic Society criteria for MUTYH/APC testing, in a tertiary center in Northern Israel and four additional gastro-genetic clinics in Israel. RESULTS: The Northern cohort included 37 patients from 30 unrelated families; 8(26.6%) carried bi-allelic MUTYH PVs. The major variant p.Glu452del was detected in 6/8 Druze and Muslim families who shared the same haplotype. Other PVs detected in both cohorts included p.Tyr56Ter, p.His57Arg, c.849+3A>C, p.Ala357fs, and p.Tyr151Cys. Among bi-allelic carriers, 88% reported consanguinity, and 100% had positive family history for polyposis or colorectal cancer (CRC). Generally, the age of CRC was 10 years younger than reported in the general MAP population. CONCLUSIONS: MAP accounted for 27% of polyposis cases in the Arab population of Northern Israel. PVs spectrum is unique, with high frequency of the founder variant p.Glu452del. Our results may inform the genetic testing strategy in the Israeli Arab population.
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Neoplasias Colorrectales , Predisposición Genética a la Enfermedad , Humanos , Niño , Israel/epidemiología , Prevalencia , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Poblaciones Minoritarias, Vulnerables y Desiguales en Salud , MutaciónRESUMEN
The tight junction proteins (TJPs) are major determinants of endothelial cells comprising physiological vascular barriers such as the blood-brain barrier, but little is known about their expression and role in immune cells. In this study we assessed TJP expression in human leukocyte subsets, their induction by immune activation and modulation associated with autoimmune disease states and therapies. A consistent expression of TJP complexes was detected in peripheral blood leukocytes (PBLs), predominantly in B and T lymphocytes and monocytes, whereas the in vitro application of various immune cell activators led to an increase of claudin 1 levels, yet not of claudin 5. Claudins 1 and 5 levels were elevated in PBLs of multiple sclerosis (MS) patients in relapse, relative to patients in remission, healthy controls and patients with other neurological disorders. Interestingly, claudin 1 protein levels were elevated also in PBLs of patients with type 1 diabetes (T1D). Following glucocorticoid treatment of MS patients in relapse, RNA levels of JAM3 and CLDN5 and claudin 5 protein levels in PBLs decreased. Furthermore, a correlation between CLDN5 pre-treatment levels and clinical response phenotype to interferon-ß therapy was detected. Our findings indicate that higher levels of leukocyte claudins are associated with immune activation and specifically, increased levels of claudin 5 are associated with MS disease activity. This study highlights a potential role of leukocyte TJPs in physiological states, and autoimmunity and suggests they should be further evaluated as biomarkers for aberrant immune activity and response to therapy in immune-mediated diseases such as MS.
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Leucocitos/metabolismo , Proteínas de la Membrana/metabolismo , Esclerosis Múltiple/metabolismo , Uniones Estrechas/metabolismo , Adulto , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The tight junctions (TJs) form continuous intracellular contacts, which help create selective barriers in epithelial and endothelial cell layers. The structures created by the TJs are very dynamic and can be rapidly remodeled in response to physiological and pathological signals. Claudin 5 is a membranal TJ protein which plays a critical role in determining the permeability of endothelial barriers. We describe the regulation of claudin 5 degradation by the ubiquitin-proteasome system (UPS). Our results indicate that claudin 5 has a relatively short half-life and can be polyubiquitinated on lysine 199. This ubiquitination appears to trigger the proteasome-dependent degradation of claudin 5. Other mechanisms also seem to be involved in the post-translational regulation of claudin 5, including a ubiquitin-independent and probably indirect lysosomal-dependent pathway. These findings provide evidence for the involvement of the UPS in the regulation of claudin 5 levels, and set the stage for further research to determine the involvement of this pathway in the modulation of the properties of TJs and cell-layer barriers.
Asunto(s)
Claudinas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitinación/fisiología , Línea Celular Tumoral , Claudina-5 , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Uniones Estrechas/fisiología , Ubiquitina/metabolismoRESUMEN
BACKGROUND: Multiple sclerosis (MS) prevalence and genetic susceptibility varies among the different ethnic groups of Jews and Arabs in Israel. OBJECTIVE: Characterization of MS disease course in Christian, Muslim and Druze Arabs in Israel. METHODS: Historical cohort and three-year follow-up cohort analyses based on interviews and clinical charts of 149 Arab MS patients (78 Muslims, 49 Christians and 22 Druze) from three MS centers in Israel. Significant findings were adjusted for use of disease modifying therapy. RESULTS: Age of onset (means between 30 and 31 years) and incomplete recovery rates after the first relapse (~50%) were similar for Christian, Muslim and Druze patients. Low rates of primary progressive MS (≤1%) were observed. Differences between the ethnicities in the time from onset to the second neurological episode were observed among females, but not males. Druze and Muslim women were more likely to have a second event within two years from the first event compared with Christians (odds ratios =8.8, p= 0.02; odds ratio=6.6, p=0.007 respectively). Trends for higher annual relapse rates, annual disability progression rates and MS Severity Scores were observed among the Druze. CONCLUSIONS: Among the Israeli Arab female MS patients, Druze and Muslims exhibit a more rapid disease course in comparison with Christians. Further elucidation of population-specific MS phenotypes may contribute to improved disease management.