RESUMEN
KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.
Asunto(s)
Epilepsias Mioclónicas Progresivas/genética , Canales de Potasio/genética , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Epilepsias Mioclónicas Progresivas/fisiopatología , Linaje , Fenotipo , Pez CebraRESUMEN
PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort. METHODS: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders. RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses. CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.
Asunto(s)
Variaciones en el Número de Copia de ADN , Mutación INDEL , Niño , Variaciones en el Número de Copia de ADN/genética , Exones , Humanos , Estudios Retrospectivos , Secuenciación del ExomaRESUMEN
BACKGROUND: The ankle and heel are challenging regions to reconstruct functionally. Here, we explored the feasibility and clinical outcomes of a modified anterior tibial artery perforator-pedicled propeller flap for the repair of soft-tissue defects of the ankle and heel. PATIENTS AND METHODS: Between January 2013 and December 2015, 12 patients with soft-tissue defects of the ankle and/or heel underwent reconstructive surgery that included our flap technique. The flaps measured 20 × 8 cm to 7 × 4 cm. A hand-held Doppler was used to identify a proper constant perforator in the distal ankle. In each case, the base of the flap was well preserved. The flap was transposed (180° rotation) to reach and cover the defect. RESULTS: The average follow-up time was 13 months (10-28 months). We observed good texture matches and contour in all of the flaps. All patients could walk and wear normal footwear. All but one flap survived completely without complications. Partial loss was observed in one patient, and the necrotic region was healed with secondary intention. CONCLUSION: Our modified anterior tibial artery free-style perforator-pedicled propeller flap provides a novel option for functional ankle and heel reconstruction. LEVEL OF EVIDENCE: Level IV.
Asunto(s)
Tobillo/cirugía , Talón/cirugía , Colgajo Perforante , Procedimientos de Cirugía Plástica/métodos , Traumatismos de los Tejidos Blandos/cirugía , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Colgajo Perforante/irrigación sanguínea , Colgajo Perforante/cirugía , Estudios Retrospectivos , Arterias Tibiales/cirugía , Adulto JovenRESUMEN
Canine cholelithiasis is considered to be an uncommon condition and is frequently cited as being an incidental finding. However, there is a paucity of contemporary literature to support these assertions. The aim of this retrospective cross-sectional study was to report the prevalence, clinical presentation, and long-term follow-up of cholelithiasis in dogs. The electronic database at the Small Animal Hospital, University of Glasgow was searched to identify dogs that were diagnosed with cholelithiasis on ultrasound between 2010 and 2018. Sixty-eight dogs were identified, giving an overall prevalence of cholelithiasis in our hospital of 0.97% (confidence interval 0.76-1.22%). Medical records of 61 dogs were available for review. Cholelithiasis was classified as an incidental finding in 53 (86.9%) dogs, with 8 (13.1%) dogs being classified as symptomatic, having complications of cholelithiasis that included biliary duct obstruction, biliary peritonitis, emphysematous cholecystitis, and acute cholecystitis. Follow-up was available for 39 dogs, with only 3 dogs (7.7%) developing complications attributed to cholelithiasis, including biliary duct obstruction and acute cholecystitis, within the subsequent 2 yr. Cholelithiasis is an uncommon but frequently incidental finding in dogs. Within the follow-up period, few of the dogs with incidental cholelithiasis went on to be become symptomatic.
Asunto(s)
Colelitiasis/veterinaria , Enfermedades de los Perros/epidemiología , Animales , Colelitiasis/epidemiología , Estudios Transversales , Perros , Femenino , Masculino , Prevalencia , Registros/veterinaria , Estudios Retrospectivos , Factores de Riesgo , Escocia/epidemiologíaRESUMEN
PURPOSE: Clinical laboratories performing exome or genome sequencing (ES/GS) are familiar with the challenges associated with proper consenting for and reporting of medically actionable secondary findings based on recommendations from the American College of Medical Genetics and Genomics (ACMG). Misattributed parentage is another type of unanticipated finding a laboratory may encounter during family-based ES/GS; however, there are currently no professional recommendations related to the proper consenting for and reporting of misattributed parentage encountered during ES/GS. METHODS: We surveyed 10 clinical laboratories offering family-based ES/GS regarding their consent language, discovery, and reporting of misattributed parentage. RESULTS: Many laboratories have already developed their own practices/policies for these issues, which do not necessarily agree with those from other labs. CONCLUSION: There are several other possibilities besides true misattributed parentage that could result in similar laboratory findings, and laboratories often feel they lack sufficient information to make formal conclusions on a report regarding the true genetic relatedness of the submitted samples. However, understanding the genetic relatedness (or lack thereof) of the samples submitted for family-based ES/GS has medical relevance. Therefore, professional recommendations for the appropriate handling of suspected misattributed parentage encountered during ES/GS are needed to help standardize current clinical laboratory practices.
Asunto(s)
Pruebas Genéticas/tendencias , Genética Médica/tendencias , Genómica/tendencias , Padres , Servicios de Laboratorio Clínico , Exoma/genética , Femenino , Genoma Humano/genética , Humanos , Hallazgos Incidentales , Consentimiento Informado , Masculino , Encuestas y Cuestionarios , Secuenciación del Exoma/tendencias , Secuenciación Completa del Genoma/tendenciasRESUMEN
There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.
Asunto(s)
Secuenciación del Exoma , Enfermedades Raras/diagnóstico , Enfermedades no Diagnosticadas/genética , Exoma , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fenotipo , Enfermedades Raras/genética , Análisis de Secuencia de ADNRESUMEN
Brief neuronal activation in injured peripheral nerves is both necessary and sufficient to enhance motor axon regeneration, and this effect is specific to the activated motoneurons. It is less clear whether sensory neurons respond in a similar manner to neuronal activation following peripheral axotomy. Further, it is unknown to what extent enhancement of axon regeneration with increased neuronal activity relies on a reflexive interaction within the spinal circuitry. We used mouse genetics and optical tools to evaluate the precision and selectivity of system-specific neuronal activation to enhance axon regeneration in a mixed nerve. We evaluated sensory and motor axon regeneration in two different mouse models expressing the light-sensitive cation channel, channelrhodopsin (ChR2). We selectively activated either sensory or motor axons using light stimulation combined with transection and repair of the sciatic nerve. Regardless of genotype, the number of ChR2-positive neurons whose axons had regenerated successfully was greater following system-specific optical treatment, with no effect on the number of ChR2-negative neurons (whether motor or sensory neurons). We conclude that acute system-specific neuronal activation is sufficient to enhance both motor and sensory axon regeneration. This regeneration-enhancing effect is likely cell autonomous.
Asunto(s)
Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/metabolismo , Nervio Ciático/metabolismo , Células Receptoras Sensoriales/metabolismo , Animales , Axones/fisiología , Axotomía/métodos , Femenino , Masculino , Ratones Transgénicos , Neuronas Motoras/fisiologíaRESUMEN
Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.
Asunto(s)
Trastorno del Espectro Autista/genética , Proteínas Portadoras/genética , Facies , Haploinsuficiencia , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Trastorno del Espectro Autista/complicaciones , Niño , Preescolar , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Trastornos del Desarrollo del Lenguaje/complicaciones , MasculinoRESUMEN
BACKGROUND: Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management. OBJECTIVE: The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies. STUDY DESIGN: We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data. RESULTS: The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY. CONCLUSION: The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.
Asunto(s)
Ácidos Nucleicos Libres de Células/sangre , Trastornos de los Cromosomas/sangre , Amniocentesis , Síndrome de Angelman/sangre , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Muestra de la Vellosidad Coriónica , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Cromosomas Humanos X/genética , Síndrome del Maullido del Gato/sangre , Síndrome del Maullido del Gato/diagnóstico , Síndrome del Maullido del Gato/genética , Síndrome de Down/sangre , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Síndrome de Klinefelter/sangre , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Análisis por Micromatrices , Síndrome de Prader-Willi/sangre , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Valor Predictivo de las Pruebas , Embarazo , Diagnóstico Prenatal , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/sangre , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genética , Trisomía/diagnóstico , Trisomía/genética , Síndrome de la Trisomía 13/sangre , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 13/genética , Síndrome de la Trisomía 18/sangre , Síndrome de la Trisomía 18/diagnóstico , Síndrome de la Trisomía 18/genética , Síndrome de Turner/sangre , Síndrome de Turner/diagnóstico , Síndrome de Turner/genéticaRESUMEN
BACKGROUND: Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS: We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS: We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS: Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.).
Asunto(s)
Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Pruebas Genéticas/métodos , Análisis de Secuencia de ADN/métodos , Adolescente , Niño , Preescolar , Genes Dominantes , Genes Recesivos , Genes Ligados a X , Enfermedades Genéticas Congénitas/genética , Humanos , Mutación , Fenotipo , Adulto JovenRESUMEN
Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB(-/-) mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons.
Asunto(s)
Neuronas Motoras/metabolismo , Receptor trkB/metabolismo , Transducción de Señal/fisiología , Sinapsis/metabolismo , Animales , Femenino , Masculino , Ratones Transgénicos , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteínas de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Electrical stimulation and exercise are treatments to enhance recovery from peripheral nerve injuries. Brain-derived neurotrophic factor and androgen receptor signaling are requirements for the effectiveness of these treatments. Increased neuronal activity is adequate to promote regeneration in injured nerves, but the dosing of activity and its relationship to neurotrophins and sex steroid hormones is less clear. Translation of these therapies will require principles associated with their cellular mechanisms.
Asunto(s)
Axones , Terapia por Estimulación Eléctrica , Terapia por Ejercicio , Factores de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/terapia , Nervios Periféricos/fisiopatología , Animales , Axones/metabolismo , Axones/patología , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Masculino , Traumatismos de los Nervios Periféricos/diagnóstico , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/fisiopatología , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Recuperación de la Función , Transducción de Señal , Resultado del TratamientoRESUMEN
Angelman syndrome is a neurodevelopmental disorder caused by a deficiency of the imprinted and maternally expressed UBE3A gene. Although de novo genetic and epigenetic imprinting defects of UBE3A genomic locus account for majority of Angelman diagnoses, approximately 10% of individuals affected with Angelman syndrome are a result of UBE3A loss-of-function mutations occurring on the expressed maternal chromosome. The variants described in this manuscript represent the analysis of 2,515 patients referred for UBE3A gene sequencing at our institution, along with a comprehensive review of the UBE3A mutation literature. Of these, 267 (10.62%) patients had a report issued for detection of a UBE3A gene nucleotide variant, which in many cases involved family studies resulting in reclassification of variants of unknown clinical significance (VUS). Overall, 111 (4.41%) probands had a nucleotide change classified as pathogenic or strongly favored to be pathogenic, 29 (1.15%) had a VUS, and 126 (5.0%) had a nucleotide change classified as benign or strongly favored to be benign. All variants and their clinical interpretations are submitted to NCBI ClinVar, a freely accessible human variation and phenotype database.
Asunto(s)
Síndrome de Angelman/genética , Mutación , Ubiquitina-Proteína Ligasas/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
OBJECTIVE: Estimating dietary intake is challenging in patients with chronic diseases. The aim of this study was to calibrate the Block Brief 2000 food frequency questionnaire (BFFQ) using 3-day food diary records among patients on dialysis. METHODS: Data from 3-day food diary records from 146 patients new to dialysis were reviewed and entered into National Cancer Institute self-administered 24-hour dietary recall (ASA24), a web-based dietary interview system. The information was then re-entered omitting foods reported in the diaries that were not in the BFFQ to generate a "BFFQ-restricted" set of intakes. We modeled each major dietary component (i.e., energy [total calories], protein, carbohydrate, fat) separately using linear regression. The main independent variables were BFFQ-restricted food diary estimates computed as the average of the 3 days of diaries, restricted to items included in the BFFQ, with the unrestricted 3-day food diary averages as dependent variables. RESULTS: The BFFQ-restricted diary energy estimate of 1,325 ± 545 kcal was 87% of the energy intake in the full food diary (1,510.3 ± 510.4, P < .0001). The BFFQ-restricted diary carbohydrate intake was 83% of the full food diary (156.7 ± 78.7 g vs. 190.4 ± 72.7, P < .0001). The BFFQ-restricted fat intake was 90% of the full-diary-reported fat intake (50.1 ± 24.1 g vs. 56.4 ± 21.6 g, P < .0001). Daily protein intake assessments were not statistically different by BFFQ-restricted diary and full diary assessment (63.1 ± 28.5 vs. 64.1 ± 21.4 g, P = .60). The associations between BFFQ-restricted diary intake and unrestricted intake were linear. Three-day diary-reported intake could be estimated from BFFQ-restricted intake with r2 ranging from 0.36 to 0.56 (P < .0001 for energy [total calories], protein, carbohydrate, and fat). Final equations did not include adjustments for age, sex, or race because the patterns of associations were not significantly different. CONCLUSION: Energy and macronutrient estimates by BFFQ are lower than estimates from 3-day food diaries, but simple calibration equations can be used to approximate total intake from BFFQ responses.
Asunto(s)
Dieta , Diálisis Renal , Encuestas y Cuestionarios , Adulto , Anciano , Anciano de 80 o más Años , Calibración , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Humanos , Masculino , Persona de Mediana Edad , National Cancer Institute (U.S.) , Evaluación Nutricional , Insuficiencia Renal Crónica , Estados UnidosRESUMEN
IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
Asunto(s)
Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Técnicas de Diagnóstico Molecular , Análisis de Secuencia de ADN/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Feto , Pruebas Genéticas , Genómica , Humanos , Hallazgos Incidentales , Lactante , Recién Nacido , Masculino , Mutación , Fenotipo , Derivación y ConsultaRESUMEN
Peripheral nerve injuries are common, and full functional recovery after injury is achieved in only 10% of patients. The sympathetic nervous system plays many critical roles in maintaining bodily homeostasis, but it has rarely been studied in the context of peripheral nerve injury. The extent of postganglionic sympathetic neuronal functions in distal targets in the periphery is currently unclear. To better explore the role of sympathetic innervation of peripheral targets, a surgical "knock-out" model provides an alternative approach. Although this can be achieved chemically, chemical destruction of postganglionic sympathetic neurons can be nonspecific and dose-dependent. The use of a surgical lumbar sympathectomy in mice, once thought to be "virtually not practicable" in small animals, allows for specific targeting of postganglionic sympathetic neurons that innervate the hind limbs. This manuscript describes how to surgically remove the L2-L5 lumbar sympathetic ganglia from a mouse as a survival surgery, which reliably decreases the hind paw sweat response and the number of sympathetic axons in the sciatic nerve.
Asunto(s)
Simpatectomía , Animales , Ratones , Simpatectomía/métodos , Ganglios Simpáticos/cirugía , Región Lumbosacra/inervación , Región Lumbosacra/cirugía , Nervio Ciático/cirugía , Nervio Ciático/lesiones , Miembro Posterior/inervación , Miembro Posterior/cirugíaRESUMEN
Appendiceal mucinous neoplasms (AMNs) are uncommon gastrointestinal tumors characterized by mucus accumulation in the appendix. Patients may complain of acute appendicitis-like symptoms with other alarming features, but approximately half of the cases of AMNs are found incidentally on imaging. Early diagnosis and management of these neoplasms are important to prevent malignant progression and complications such as bowel obstruction and pseudomyxoma peritonei. We report a case of a 28-year-old female who initially presented with vomiting and acute left lower abdominal pain radiating to the left flank. Computed tomography (CT) revealed a 1.5 mm stone in the left ureteral vesicular junction and a 2.3 x 2.4 x 5.2 cm cystic tubular mass at the base of the cecum, suspicious of an appendiceal mucocele. An elective laparoscopic appendectomy was performed on this admission, which was converted to a right hemicolectomy due to the pathologic finding of a focally high-grade AMN on intraoperative frozen specimen pathology. This report aims to provide an example of a case of an incidental AMN and how it was diagnosed and managed surgically. AMNs are rare tumors that originate from the appendix and can pose diagnostic and therapeutic challenges due to their diverse clinical presentations and variable histopathological features. The majority of cases of AMNs are discovered in middle-aged individuals (40-50 years of age) after an appendectomy is performed and examined by pathology. This case report aims to describe a rare presentation of a 28-year-old female patient with an incidental finding of AMN on a CT scan of the abdomen while being worked up for suspected nephrolithiasis. We will provide a comprehensive overview of a unique presentation of AMN, highlighting its clinical manifestations, diagnostic approach, and management strategies. We present the case of a 28-year-old female patient who presented to the emergency department with complaints of acute left lower quadrant abdominal pain radiating to the left flank and vomiting. After an initial assessment and workup, which included lab investigations and imaging, a diagnosis of unilateral hydronephrosis due to a calculus of the ureterovesical junction was made. However, there was also suspicion of an appendiceal mucocele, as evidenced by a CT scan of the abdomen and pelvis. On admission day one, under the care and management of the urology team, she passed the stone with complete resolution of the presenting symptoms. On hospital day two, she underwent an elective laparoscopic appendectomy followed by a right hemicolectomy due to findings of high-grade mucinous neoplasm on the resected frozen specimen near the base of the appendix. AMN was an incidental finding based on CT imaging and macroscopic findings, which was later confirmed by histopathological assessment and report.
RESUMEN
Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.