RESUMEN
Biallelic disease-causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi-centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients. Genetic testing using targeted next generation sequencing was performed in 16 183 cardiomyopathy index cases. Thirty-six patients carried at least one null ALPK3 variant. The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest). The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy. Reporting a large cohort of ALPK3 patients, this collaborative work confirmed a strong association with HCM and suggesting his screening in the context of idiopathic HCM.
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Cardiomiopatía Hipertrófica , Proteínas Musculares , Fenotipo , Proteínas Quinasas , Humanos , Cardiomiopatía Hipertrófica/genética , Masculino , Femenino , Adulto , Niño , Adolescente , Francia/epidemiología , Persona de Mediana Edad , Prevalencia , Mutación , Preescolar , Predisposición Genética a la Enfermedad , Estudios de Cohortes , Heterocigoto , Adulto Joven , Pruebas Genéticas , Lactante , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , AncianoRESUMEN
Xq28 int22h-1/int22h-2 duplication is the result of non-allelic homologous recombination between int22h-1/int22h-2 repeats separated by 0.5 Mb. It is responsible for a syndromic form of intellectual disability (ID), with recurrent infections and atopic diseases. Minor defects, nonspecific facial dysmorphic features, and overweight have also been described. Half of female carriers have been reported with ID, whereas all reported evaluated born males present mild to moderate ID, suggesting complete penetrance. We collected data on 15 families from eight university hospitals. Among them, 40 patients, 21 females (one fetus), and 19 males (two fetuses), were carriers of typical or atypical Xq28 int22h-1/int22h-2 duplication. Twenty-one individuals were considered asymptomatic (16 females and 5 males), without significantly higher rate of recurrent infections, atopia, overweight, or facial dysmorphism. Approximately 67% live-born males and 23% live-born female carriers of the typical duplication did not have obvious signs of intellectual disability, suggesting previously undescribed incomplete penetrance or low expression in certain carriers. The possibility of a second-hit or modifying factors to this possible susceptibility locus is yet to be studied but a possible observational bias should be considered in assessing such challenging X-chromosome copy number gains. Additional segregation studies should help to quantify this newly described incomplete penetrance.
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Cromosomas Humanos X , Discapacidad Intelectual , Penetrancia , Humanos , Masculino , Femenino , Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Niño , Adulto , Adolescente , Preescolar , Fenotipo , Duplicación Cromosómica/genética , Duplicación de Gen , Linaje , Adulto JovenRESUMEN
Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.
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Aneuploidia , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Anomalías del Ojo , Cardiopatías Congénitas , Humanos , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Cromosomas Humanos Par 22/genética , Cardiopatías Congénitas/genéticaRESUMEN
Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.
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Duplicación Cromosómica , Cromosomas Humanos Par 3 , Variaciones en el Número de Copia de ADN , Fenotipo , Humanos , Femenino , Masculino , Cromosomas Humanos Par 3/genética , Duplicación Cromosómica/genética , Niño , Variaciones en el Número de Copia de ADN/genética , Preescolar , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Adolescente , Estudios de Cohortes , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Adulto , LactanteRESUMEN
Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non-histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY-1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy in the treatment of malignant diseases, but anaemia is one of the most frequent side effects. We investigated here the underlying mechanisms of this erythroid toxicity. We first confirmed that HDAC6 was strongly expressed at both RNA and protein levels in CD34+ -cells-derived erythroid progenitors. ACY-1215 exposure on CD34+ -cells driven in vitro towards the erythroid lineage led to a decreased cell count, an increased apoptotic rate and a delayed erythroid differentiation with accumulation of weakly hemoglobinized immature erythroblasts. This was accompanied by drastic changes in the transcriptomic profile of primary cells as shown by RNAseq. In erythroid cells, ACY-1215 and shRNA-mediated HDAC6 knockdown inhibited the EPO-dependent JAK2 phosphorylation. Using acetylome, we identified 14-3-3ζ, known to interact directly with the JAK2 negative regulator LNK, as a potential HDAC6 target in erythroid cells. We confirmed that 14-3-3ζ was hyperacetylated after ACY-1215 exposure, which decreased the 14-3-3ζ/LNK interaction while increased LNK ability to interact with JAK2. Thus, in addition to its previously described role in the enucleation of mouse fetal liver erythroblasts, we identified here a new mechanism of HDAC6-dependent control of erythropoiesis through 14-3-3ζ acetylation level, LNK availability and finally JAK2 activation in response to EPO, which is crucial downstream of EPO-R activation for human erythroid cell survival, proliferation and differentiation.
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Proteínas 14-3-3 , Transducción de Señal , Ratones , Animales , Humanos , Proteínas 14-3-3/metabolismo , Ácidos Hidroxámicos/farmacología , Diferenciación Celular/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismoRESUMEN
OBJECTIVE: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes. METHODS: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France. RESULTS: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated. CONCLUSION: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.
Asunto(s)
Síndrome de Williams , Humanos , Femenino , Embarazo , Síndrome de Williams/diagnóstico por imagen , Síndrome de Williams/genética , Síndrome de Williams/complicaciones , Variaciones en el Número de Copia de ADN , Estudios Retrospectivos , Retardo del Crecimiento Fetal , UltrasonografíaRESUMEN
Acute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques.
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Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Adolescente , Adulto , Biomarcadores de Tumor/genética , Niño , Preescolar , Mapeo Cromosómico , Análisis Citogenético , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Adulto JovenRESUMEN
Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , N-Metiltransferasa de Histona-Lisina/genética , Discapacidad Intelectual/genética , Megalencefalia/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Deleción Cromosómica , Cromosomas Humanos Par 9/genética , Hibridación Genómica Comparativa , Anomalías Craneofaciales/complicaciones , Anomalías Craneofaciales/patología , Femenino , Asesoramiento Genético , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Masculino , Megalencefalia/patología , Mosaicismo , Mutación , Fenotipo , Adulto JovenRESUMEN
Facial femoral syndrome (FFS) is a rare congenital abnormality, also known as femoral hypoplasia-unusual facies syndrome, characterized by variable degrees of femoral hypoplasia, associated with specific facial features. Other organ malformations are sometimes present. Most cases are sporadic, but rare family observations suggest genetic origin. However, no chromosomal or genetic abnormalities have ever been incriminated. We conducted a comprehensive literature review and added three new unreported observations. Through these 92 cases, authors aimed to determine sonographic signs that should direct towards diagnosis, and discuss potential genetic etiology. Diagnosis was suspected prenatally in 27.2% of cases, and maternal diabetes was found in 42.4% of patients. When fetal karyotype was available, it was normal in 97.1% of cases, but genomic variations of unknown significance were discovered in all three cases in which array comparative genomic hybridization (CGH) techniques were applied. Femoral affection defining FFS was hypoplasia in 78.3% of cases, agenesis in 12%, and both in 9.8%. Affection was bilateral in 84.8% of cases. Retrognathia was present in 65.2% of cases, cleft lip and/or palate in 63%, and other organ malformations in 53.3%. Intellectual development was normal in 79.2% of cases. Better prenatal recognition of this pathology, notably frequently associated malformations, should lead to a more precise estimation of functional prognosis. It seems likely that today's tendency to systematically employ array-CGH and exome/genome sequencing methods to investigate malformative sequences will allow the identification of a causal genetic abnormality in the near future.
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Anomalías Múltiples/diagnóstico , Fémur/anomalías , Síndrome de Pierre Robin/diagnóstico , Diagnóstico Prenatal , Ultrasonografía Prenatal/métodos , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adulto , Labio Leporino/diagnóstico , Labio Leporino/diagnóstico por imagen , Labio Leporino/genética , Labio Leporino/fisiopatología , Hibridación Genómica Comparativa , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/diagnóstico por imagen , Diabetes Gestacional/fisiopatología , Femenino , Fémur/diagnóstico por imagen , Fémur/fisiopatología , Feto , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Síndrome de Pierre Robin/diagnóstico por imagen , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/fisiopatología , EmbarazoRESUMEN
Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.
Asunto(s)
Reordenamiento Génico , Enanismo Mulibrey/genética , Mutación , Proteínas Nucleares/genética , Adolescente , Niño , Preescolar , Femenino , Francia , Humanos , Lactante , Masculino , Enanismo Mulibrey/patología , Pronóstico , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Mosaicism for an autosomal structural rearrangement that does not involve ring or marker chromosomes is rare. The mechanisms responsible for genome instability have not always been explained. Several studies have shown that interstitial telomeric sequences (ITSs), involved in some mosaic constitutional anomalies, are potent sources of genomic instability. Here we describe two cases of mosaicism for uncommon constitutional autosomal rearrangements, involving ITSs, identified by karyotyping and characterized by FISH and SNP-array analysis. The first patient, a boy with global developmental delay, had a rare type of pure distal 1q inverted duplication (1q32-qter), attached to the end of the short arm of the same chromosome 1, in approximately 35% of his cells. The second patient, a phenotypically normal man, was diagnosed as having mosaic for a balanced non-reciprocal translocation of the distal segment of 7q (7q33qter), onto the terminal region of the short arm of a whole chromosome 12, in approximately 80% of his cells. The remaining 20% of the cells showed an unbalanced state of the translocation, with only the der(7) chromosome. He was ascertained through his malformed fetus carrying a non-mosaic partial monosomy 7q, identified at prenatal diagnosis. We show that pan-telomeric and subtelomeric sequences were observed at the interstitial junction point of the inv dup(1q) and of the der(12)t(7;12), respectively. The present cases and review of the literature suggest that the presence of ITSs at internal sites of the chromosomes may explain mechanisms of the patients's mosaic structural rearrangements.
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Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Mosaicismo , Telómero/genética , Translocación Genética , Adulto , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Interstitial microdeletions of 20q chromosome are rare, only 17 patients have been reported in the literature to date. Among them, only six carried a proximal 20q11.21-q11.23 deletion, with a size ranging from 2.6 to 6.8 Mb. The existence of a 20q11.2 microdeletion syndrome has been proposed, based on five previously reported cases that displayed anomalies of the extremities, intellectual disability, feeding difficulties, craniofacial dysmorphism and variable malformations. To further characterize this syndrome, we report on six new patients with 20q11.2 microdeletions diagnosed by whole-genome array-based comparative genomic hybridization. These patient reports more precisely refined the phenotype and narrowed the minimal critical region involved in this syndrome. Careful clinical assessment confirms the distinctive clinical phenotype. The craniofacial dysmorphism consists of high forehead, frontal bossing, enophthalmos, and midface hypoplasia. We have identified a 1.62 megabase minimal critical region involved in this syndrome encompassing three genesGDF5, EPB41L1, andSAMHD1which are strong candidates for different aspects of the phenotype. These results support that 20q11.2 microdeletion syndrome is a new contiguous gene deletion syndrome with a recognizable phenotype.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 20 , Fenotipo , Adolescente , Niño , Preescolar , Aberraciones Cromosómicas , Puntos de Rotura del Cromosoma , Hibridación Genómica Comparativa , Facies , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Cariotipificación , Masculino , Síndrome , Adulto JovenRESUMEN
Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.
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Trastornos de las Plaquetas Sanguíneas/genética , Dislexia/genética , Ictiosis/genética , Proteínas de la Membrana/genética , Trastornos Migrañosos/genética , Miosis/genética , Proteínas de Neoplasias/genética , Mutación Puntual , Bazo/anomalías , Adolescente , Adulto , Anciano , Trastornos de las Plaquetas Sanguíneas/metabolismo , Trastornos de las Plaquetas Sanguíneas/patología , Calcio/metabolismo , Canales de Calcio/metabolismo , Niño , Preescolar , Dislexia/metabolismo , Dislexia/patología , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/ultraestructura , Eritrocitos Anormales/metabolismo , Eritrocitos Anormales/patología , Femenino , Humanos , Ictiosis/metabolismo , Ictiosis/patología , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/patología , Miosis/metabolismo , Miosis/patología , Fatiga Muscular/genética , Fibras Musculares Esqueléticas/patología , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Linaje , Estructura Secundaria de Proteína , Bazo/metabolismo , Bazo/patología , Molécula de Interacción Estromal 1RESUMEN
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) -OMIM 312870- is a rare X-linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmorphism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient's liver disease is also proposed.
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Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Gigantismo/diagnóstico , Gigantismo/terapia , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/terapia , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/terapia , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/terapia , Trasplante de Hígado , Arritmias Cardíacas/genética , Biopsia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Gigantismo/genética , Glipicanos/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Hígado/patología , Cirrosis Hepática Biliar/genética , Masculino , Mutación , Fenotipo , Resultado del TratamientoRESUMEN
Severe Alcoholic Hepatitis (sAH) is an acute form of liver injury caused by chronic and heavy alcohol drinking. A one-month corticosteroids course is the only sAH reference treatment, and its interactions with the Gut Microbiota (GM), which is a key contributor to liver injury, remain unknown. To evaluate the evolution of the GM in sAH patients, we retrospectively investigated the composition of the GM of 27 sAH patients at the Amiens University Hospital before (D0) and after (D7) a 7-day corticotherapy course using fecal metagenomics sequencing. We also quantified fecal Short-Chain Fatty Acids (SCFA) and fecal and serum Bile Acids (BA), as well as serum Lipopolysaccharide-Binding Protein (LBP). Overall, the community and taxonomical analyses did not reveal any GM evolution between D0 and D7, nor did the SCFA profiles analysis. However, in serum but not fecal samples, the ratio of glyco-conjugated to tauro-conjugated BA was significantly reduced at D7, independently of the response to treatment, while two BA were enriched in non-responder patients. LBP concentration significantly diminished between D0 and D7, which may indicate an improvement of the gut barrier. The stability of the GM of sAH is interesting in the perspective of new treatments based on GM modulation.
There is a gap in the understanding of the effects of corticosteroids on the gut microbiota of severe alcoholic hepatitis patients.In this study, the composition of the Gut Microbiota of sAH patients treated with prednisolone remains unchanged after 7 days of prednisolone treatment.Short-Chain Fatty Acid profiles are not impacted by the treatment, while Bile Acids profiles change in serum but not in stool samples.Responders and non-responders show different lipopolysaccharide-binding protein serum concentration evolution across time, as well as distinct Bile Acid profiles.
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Ácidos y Sales Biliares , Heces , Microbioma Gastrointestinal , Hepatitis Alcohólica , Prednisolona , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/sangre , Masculino , Heces/microbiología , Heces/química , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Prednisolona/administración & dosificación , Adulto , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/efectos de los fármacos , Ácidos Grasos Volátiles/metabolismo , Ácidos Grasos Volátiles/sangre , Proteínas Portadoras/genética , Proteínas Portadoras/sangre , Proteínas de Fase Aguda/metabolismo , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , Anciano , MetagenómicaRESUMEN
Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype-tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double-strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p-H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin-dependent kinase 1 (CDK1)-cyclin B1 and M-phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells.
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Apoptosis , Ciclo Celular , Leucemia Mieloide Aguda , Monocitos , Molécula de Interacción Estromal 2 , Humanos , Apoptosis/genética , Monocitos/metabolismo , Monocitos/patología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Molécula de Interacción Estromal 2/metabolismo , Molécula de Interacción Estromal 2/genética , Ciclo Celular/genética , Proliferación Celular , Línea Celular Tumoral , Diferenciación Celular , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Femenino , MasculinoRESUMEN
BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.
Asunto(s)
Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Muerte Súbita del Lactante , Fibrilación Ventricular , Masculino , Lactante , Humanos , Adulto , Persona de Mediana Edad , Cardiomiopatía Dilatada/genética , Prevalencia , Cardiomiopatías/diagnóstico , Fenotipo , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/complicaciones , Muerte Súbita Cardíaca/etiología , Pronóstico , Proteínas de Microfilamentos/genéticaRESUMEN
Background and Objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.
RESUMEN
BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of SCN5A in dilated cardiomyopathies (DCM) remains controversial. OBJECTIVE: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960), if not questionable.