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This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.
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Discapacidades del Desarrollo , Secuenciación del Exoma , Discapacidad Intelectual , Fenotipo , Humanos , Secuenciación del Exoma/métodos , Discapacidades del Desarrollo/genética , Niño , Masculino , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Femenino , Preescolar , Lactante , Adolescente , Pruebas Genéticas/métodosRESUMEN
BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
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Paraplejía Espástica Hereditaria , Humanos , Femenino , Adulto , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/patología , Exones , Proteínas/genética , Codón sin Sentido , Cuerpo Calloso/patología , Cuerpo Calloso/diagnóstico por imagen , Eliminación de Secuencia , FenotipoRESUMEN
The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient's fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient's fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype-phenotype correlation and the underlying mechanisms of this novel phenotype.
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Discapacidad Intelectual , Microscopía , Humanos , Masculino , Ojo , Fibroblastos , Proteína Fosfatasa 2/genética , Factores de TranscripciónRESUMEN
X-linked myopathy with excessive autophagy is a rare inherited disease characterized by aberrant accumulation of autophagic vacuoles in skeletal muscle. Affected males usually show a slow progression and the heart is characteristically spared. We present four male patients from the same family with an extremely aggressive form of this disease, requiring permanent mechanical ventilation from birth. Ambulation was never achieved. Three died, one in the first hour of life, one at 7 years and one at 17 years, the last death being a consequence of heart failure. Muscle biopsy showed pathognomonic features of the disease in the 4 affected males. Genetic study found a novel synonymous variant in VMA21, c.294C>T (Gly98=). Genotyping was consistent with co-segregation with the phenotype in an X-linked recessive manner. An alteration of the normal splice pattern was confirmed by transcriptome analysis, proving that the apparently synonymous variant was the cause of this extremely severe phenotype.
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Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
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Ceramidas , Esfingolípidos , Humanos , Ceramidas/metabolismo , Homeostasis , Mutación , Esfingolípidos/genética , Esfingolípidos/metabolismoRESUMEN
The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation.
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Epilepsia , Discapacidad Intelectual , Receptores de N-Metil-D-Aspartato , Humanos , Epilepsia/genética , Mutación Missense/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.
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Genoma Humano , Haplotipos , Mutación INDEL , Aciltransferasas , Europa (Continente) , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lipasa , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma/métodosRESUMEN
Predicting the therapeutic response to ocular hypotensive drugs is crucial for the clinical treatment and management of glaucoma. Our aim was to identify a possible genetic contribution to the response to current pharmacological treatments of choice in a white Mediterranean population with primary open-angle glaucoma (POAG) or ocular hypertension (OH). We conducted a prospective, controlled, randomized, partial crossover study that included 151 patients of both genders, aged 18 years and older, diagnosed with and requiring pharmacological treatment for POAG or OH in one or both eyes. We sought to identify copy number variants (CNVs) associated with differences in pharmacological response, using a DNA pooling strategy of carefully phenotyped treatment responders and non-responders, treated for a minimum of 6 weeks with a beta-blocker (timolol maleate) and/or prostaglandin analog (latanoprost). Diurnal intraocular pressure reduction and comparative genome wide CNVs were analyzed. Our finding that copy number alleles of an intronic portion of the MLIP gene is a predictor of pharmacological response to beta blockers and prostaglandin analogs could be used as a biomarker to guide first-tier POAG and OH treatment. Our finding improves understanding of the genetic factors modulating pharmacological response in POAG and OH, and represents an important contribution to the establishment of a personalized approach to the treatment of glaucoma.
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Proteínas Co-Represoras/genética , Glaucoma de Ángulo Abierto/patología , Hipertensión Ocular/patología , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Alelos , Biomarcadores/metabolismo , Estudios Cruzados , Variaciones en el Número de Copia de ADN , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma de Ángulo Abierto/genética , Humanos , Presión Intraocular/efectos de los fármacos , Latanoprost/farmacología , Latanoprost/uso terapéutico , Masculino , Persona de Mediana Edad , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/genética , Estudios Prospectivos , Timolol/farmacología , Timolol/uso terapéuticoRESUMEN
BACKGROUND: Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous. PATIENT AND METHODS: In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole-exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein. RESULTS: A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C-terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild-type VRK1. CONCLUSION: The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.
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Cuerpos Enrollados , Péptidos y Proteínas de Señalización Intracelular/genética , Atrofia Muscular Espinal/enzimología , Atrofia Muscular Espinal/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Consanguinidad , Humanos , MasculinoRESUMEN
Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis.
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Enfermedad de Alzheimer/genética , Estudios de Asociación Genética/métodos , Variación Genética , Mutación , Presenilina-1/genética , Proteína que Contiene Valosina/genética , Transportadoras de Casetes de Unión a ATP/genética , Femenino , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Receptores Inmunológicos/genética , Estudios Retrospectivos , Riesgo , Factores de Riesgo , Proteína Sequestosoma-1/genética , España , Secuenciación del ExomaAsunto(s)
Genes Ligados a X/genética , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Mutación Missense , Fenotipo , Quinasas p21 Activadas/genética , Adolescente , Trastorno Autístico , Femenino , Genómica , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Linaje , Quinasas p21 Activadas/metabolismoRESUMEN
Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.
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Hígado/metabolismo , Síndrome Metabólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , S-Adenosilmetionina/metabolismo , Selenio/deficiencia , Vitamina E/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Cricetinae , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Humanos , Masculino , Mesocricetus , Síndrome Metabólico/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Proteína Oncogénica p55(v-myc)/genética , Proteína Oncogénica p55(v-myc)/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Selenio/análisis , Vitamina E/análisisRESUMEN
PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.
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Braquidactilia/genética , Enanismo/genética , Discapacidad Intelectual/genética , Mutación con Pérdida de Función , Fenotipo , Proteína-Arginina N-Metiltransferasas/genética , Braquidactilia/patología , Enanismo/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , SíndromeRESUMEN
A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services.
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Variaciones en el Número de Copia de ADN , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Adolescente , Adulto , Comorbilidad , Femenino , Genotipo , Humanos , Incidencia , Discapacidad Intelectual/diagnóstico , Masculino , Trastornos Mentales/diagnóstico , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Estudios Prospectivos , España , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Microarray technology, recently implemented in international prenatal diagnosis systems, has become one of the main techniques in this field in terms of detection rate and objectivity of the results. This guideline attempts to provide background information on this technology, including technical and diagnostic aspects to be considered. Specifically, this guideline defines: the different prenatal sample types to be used, as well as their characteristics (chorionic villi samples, amniotic fluid, fetal cord blood or miscarriage tissue material); variant reporting policies (including variants of uncertain significance) to be considered in informed consents and prenatal microarray reports; microarray limitations inherent to the technique and which must be taken into account when recommending microarray testing for diagnosis; a detailed clinical algorithm recommending the use of microarray testing and its introduction into routine clinical practice within the context of other genetic tests, including pregnancies in families with a genetic history or specific syndrome suspicion, first trimester increased nuchal translucency or second trimester heart malformation and ultrasound findings not related to a known or specific syndrome. This guideline has been coordinated by the Spanish Association for Prenatal Diagnosis (AEDP, «Asociación Española de Diagnóstico Prenatal¼), the Spanish Human Genetics Association (AEGH, «Asociación Española de Genética Humana¼) and the Spanish Society of Clinical Genetics and Dysmorphology (SEGCyD, «Sociedad Española de Genética Clínica y Dismorfología¼).
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Anomalías Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos , Diagnóstico Prenatal/métodos , Anomalías Congénitas/genética , Femenino , Enfermedades Genéticas Congénitas/genética , Marcadores Genéticos , Humanos , EmbarazoRESUMEN
Next-generation sequencing (NGS) has the capacity of carrier screening in gamete donation (GD) programs. We have developed and validated an NGS carrier-screening test (qCarrier test) that includes 200 genes associated with 368 disorders (277 autosomal recessive and 37 X-linked). Carrier screening is performed on oocyte donation candidates and the male partner of oocyte recipient. Carriers of X-linked conditions are excluded from the GD program, whereas donors are chosen who do not carry mutations for the same gene/disease as the recipients. The validation phase showed a high sensitivity (>99% sensitivity) detecting all single-nucleotide variants, 13 indels, and 25 copy-number variants included in the validation set. A total of 1,301 individuals were analysed with the qCarrier test, including 483 candidate oocyte donors and 635 receptor couples, 105 females receiving sperm donation, and 39 couples seeking pregnancy. We identified 56% of individuals who are carriers for at least one genetic condition and 1.7% of female donors who were excluded from the program due to a carrier state of X-linked conditions. Globally, 3% of a priori assigned donations had a high reproductive risk that could be minimized after testing. Genetic counselling at different stages is essential for helping to facilitate a successful and healthy pregnancy.
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Tamización de Portadores Genéticos/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Variaciones en el Número de Copia de ADN , Femenino , Asesoramiento Genético , Humanos , Mutación INDEL , Masculino , Donación de Oocito , Polimorfismo de Nucleótido Simple , Salud ReproductivaRESUMEN
The purpose of this study was to determine the accuracy of autofluorescence techniques for diagnosing oral mucosa lesions, using as reference pattern for comparison the visual diagnosis made by a clinical specialist. A pilot study was conducted with 60 patients divided in a control group without mucosal pathology and a study group with known clinical history for mucosal pathology. Both groups were examined by an oral medicine specialist and by a general dentist who used VELscope(r) system, which applies tissue fluorescence visualization to identify oral mucosal abnormalities. Using the VELscope(r) system, the general dentist made overdiagnosis in two cases and underdiagnosis in one case. The sensitivity and specificity for the oral medicine specialist were 1 (95% CI: 0.884 to 1). For the general dentist, the sensitivity did not improve significantly with the use of VELscope(r) system [0.53 (95% CI: 0.343 to 0.717) versus 0.49 (95% CI: 0.406 to 0.773)] and the specificity was 0.80 (95% CI: 0.614 to 0.923). A limitation of the study is the small sample size, which does not fully represent a population and extrapolation of the data should be done carefully. Based on the obtained results, no clinical benefits were obtained using this VELscope(r) system.
Resumo O objetivo deste estudo foi determinar a precisão das técnicas de autofluorescência para o diagnóstico de lesões da mucosa oral, utilizando como padrão de referência para comparação o diagnóstico visual feito por um especialista clínico. Um estudo piloto foi realizado com 60 pacientes, divididos em um grupo controle sem patologia da mucosa oral e um grupo de estudo com história clínica conhecida de patologia da mucosa oral. Ambos os grupos foram examinados por um especialista em medicina oral e por um dentista clínico geral que usou o sistema VELscope(r), que aplica a visualização por fluorescência para identificar anormalidades do tecido da mucosa oral. Usando o sistema VELscope(r), o dentista geral realizou sobrediagnóstico em dois casos e subdiagnóstico em um caso. A sensibilidade e especificidade para o especialista em medicina oral foi 1 (IC 95%: 0,884 a 1). Para o dentista geral, a sensibilidade não melhorou significativamente com o uso do sistema de VELscope(r) [0,53 (95% CI: 0,343 to 0,717) versus 0,49 (95% CI: 0,406 to 0,773)], e a especificidade foi de 0,80 (IC de 95% : 0,614-0,923). Uma limitação do estudo é o pequeno tamanho da amostra, que não representa totalmente a população e a extrapolação dos dados deve ser feita com cuidado. Com base nos resultados obtidos, não houve benefícios clínicos com o uso do sistema VELscope(r).
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Humanos , Mucosa Bucal/patología , Estudios de Casos y Controles , Proyectos PilotoRESUMEN
Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.
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Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Dosificación de Gen , Genoma Humano , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.