RESUMEN
What is the definition of Syndrome? Since the beginning of studies in genetics, certain terminologies have been created and used to define groups of diseases or alterations. With the advancement of knowledge and the emergence of new technologies, the use of basic concepts is being done in a mistaken or often confusing way. Because of this, revisiting and readjusting the old terms becomes imminent. Here, we explore these concepts and their use, through a literature compilation of an already well-defined genetic alteration (16q11.2 microduplication). We bring comparisons in clinical and molecular scope of the alteration itself and its diagnostic methods, to improve the report of cases, rescuing terminologies and their applicability nowadays.
Asunto(s)
Cromosomas Humanos Par 16 , Humanos , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Duplicación Cromosómica , Cromosomas Humanos Par 16/genética , SíndromeRESUMEN
Pure partial duplications of the long arm of chromosome 16 are rare and few cases are described with delineation by chromosomal microarray. Data about clinical abnormalities of pure partial 16q duplications are incomplete because many individuals die during the perinatal period. We describe the clinical features of a 47-month-old Brazilian girl with 16q21q24.1 duplication. To the best of our knowledge, she is the first person with this specific chromosome segment duplication, and we compare her phenotype with the only reported individual alive with intermediate-distal pure 16q duplication.
Asunto(s)
Anomalías Múltiples/genética , Trastornos de los Cromosomas/genética , Duplicación Cromosómica , Cromosomas Humanos Par 16/genética , Brasil , Preescolar , Bandeo Cromosómico , Femenino , Humanos , FenotipoAsunto(s)
Elementos de Facilitación Genéticos , Hemoglobina H/genética , Globinas alfa/genética , Talasemia alfa/genética , Adulto , Alelos , Cromatina/genética , Cromatina/ultraestructura , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 16/ultraestructura , Eritroblastos/patología , Eritropoyesis , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Genotipo , Hemoglobina E/genética , Hemoglobina H/análisis , Humanos , Masculino , Linaje , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Eliminación de Secuencia , Suriname/etnología , Globinas alfa/biosíntesis , Talasemia alfa/sangre , Globinas beta/genéticaRESUMEN
Introducción: La leucemia mieloide aguda (LMA) es un grupo heterogéneo de desórdenes clonales con una gran variabilidad en términos de patogénesis, características morfológicas, genéticas e inmunofenotípicas. Las mutaciones en el gen NPM1 representan una de las más comunes en las LMA y está asociada con una respuesta clínica favorable. Por citogenética, la inversión del cromosoma 16 define el subgrupo de las LMA de factor de unión al grupo con un pronóstico favorable. Objetivo: Describir un caso con diagnóstico de LMA en los cuales el estudio molecular del gen NPM1 y de la inv(16) fueron positivos. Caso clínico: A nivel molecular, la hibridación in situ fluorescente fue positivo a la inv(16) y por biología molecular fue positivo tanto a la inv(16) como al gen NPM1-A, elementos de baja frecuencia de aparición. Se le administró a la paciente un esquema de poliquimioterapia no intensiva para mejorarla clínicamente. Después de una mejoría clínica inicial, la paciente comenzó con complicaciones y falleció. Conclusiones: La coexistencia de estas dos mutaciones es muy poco frecuente en pacientes con LMA, y a pesar de ser de buen pronóstico la paciente falleció a los pocos días de tratamiento(AU)
Introduction: Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders with great variability in terms of pathogenesis, morphological, genetic and immunophenotypic characteristics. NPM1 mutations represent one of the most common in AML and are associated with favorable clinical response. By cytogenetics, chromosome 16 inversion defines, with a favorable prognosis, the core‐binding factor for the subgroup of AMLs Objective: To describe a AML case in which the molecular study of the NPM1 gene and the chromosome 16 inversion were positive. Clinical case: At the molecular level, fluorescent in situ hybridization was positive for chromosome 16 inversion and, by molecular biology, it was positive for both chromosome 16 inversion and for the NPM1-A gene, elements with a low frequency of appearance. The patient was administered a non-intensive combination as part of a chemotherapy regimen to improve her clinical status. After initial clinical improvement, the patient began with complications and died. Conclusions: The coexistence of these two mutations is very rare in patients with AML. Despite presenting a good prognosis, the patient died after a few days of treatment(AU)
Asunto(s)
Humanos , Femenino , Cromosomas Humanos Par 16/genética , Leucemia Mieloide Aguda/diagnóstico , Mutación/genética , Hibridación Fluorescente in Situ/métodos , Quimioterapia Combinada , Quinasa de Linfoma Anaplásico/genéticaRESUMEN
La microdeleción 16p11.2 se relaciona, habitualmente, con discapacidad intelectual y trastornos del espectro autista. El rango fenotípico incluye un espectro que se extiende desde discapacidad intelectual con o sin autismo, alteraciones del aprendizaje y del lenguaje hasta fenotipos normales. El diagnóstico de la microdeleción se realiza mediante estudios genómicos capaces de identificar variación en número de copias, como la hibridación genómica comparativa en microarreglos, conocida como arrayCGH. Sin embargo, la predicción del fenotipo de un individuo basada únicamente en la localización de dicha deleción sigue siendo un desafío, ya que la existencia de un gran número de variantes en el genoma dificulta la interpretación de posibles efectos funcionales de los genes que contribuyen a dicha región. Se describen dos casos clínicos de pacientes con microdeleción heterocigota en 16p11.2 y se destacan los hallazgos fenotípicos y conductuales que dificultaron la estrategia diagnóstica. También se discuten las implicancias del diagnóstico para el asesoramiento genético familiar.
The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder. This microdeletion is associated with variable clinical outcome, the phenotypical spectrum ranges from intellectual disability and/or multiple congenital anomalies, autism, learning and speech problems, to a normal phenotype. Genomic testing that determines copy number of sequences, such as chromosomal microarray, is used to identify this microdeletion. However, the prediction of the individual phenotype of a patient based only on the location of such deletion remains a challenge, regarding the existence of many genomic variants that might hinder the interpretation of possible functional effects between most of the contributing genes to that region. We describe the clinical findings in two subjects with heterozygous microdeletions at 16p11.2, highlighting the phenotypic and behavioural findings that conditioned the diagnostic strategy. We also discuss the implications of diagnosis, in practical counselling situations.
Asunto(s)
Humanos , Masculino , Preescolar , Adolescente , Trastorno Autístico/genética , Cromosomas Humanos Par 16/genética , Deleción Cromosómica , Discapacidad Intelectual/genética , FenotipoRESUMEN
The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder. This microdeletion is associated with variable clinical outcome, the phenotypical spectrum ranges from intellectual disability and/or multiple congenital anomalies, autism, learning and speech problems, to a normal Microdeleción 16p11.2: primeros casos reportados en Argentina 16p11.2 Microdeletion: first report in Argentina phenotype. Genomic testing that determines copy number of sequences, such as chromosomal microarray, is used to identify this microdeletion. However, the prediction of the individual phenotype of a patient based only on the location of such deletion remains a challenge, regarding the existence of many genomic variants that might hinder the interpretation of possible functional effects between most of the contributing genes to that region. We describe the clinical findings in two subjects with heterozygous microdeletions at 16p11.2, highlighting the phenotypic and behavioural findings that conditioned the diagnostic strategy. We also discuss the implications of diagnosis, in practical counselling situations.
La microdeleción 16p11.2 se relaciona, habitualmente, con discapacidad intelectual y trastornos del espectro autista. El rango fenotípico incluye un espectro que se extiende desde discapacidad intelectual con o sin autismo, alteraciones del aprendizaje y del lenguaje hasta fenotipos normales. El diagnóstico de la microdeleción se realiza mediante estudios genómicos capaces de identificar variación en número de copias, como la hibridación genómica comparativa en microarreglos, conocida como arrayCGH. Sin embargo, la predicción del fenotipo de un individuo basada únicamente en la localización de dicha deleción sigue siendo un desafío, ya que la existencia de un gran número de variantes en el genoma dificulta la interpretación de posibles efectos funcionales de los genes que contribuyen a dicha región. Se describen dos casos clínicos de pacientes con microdeleción heterocigota en 16p11.2 y se destacan los hallazgos fenotípicos y conductuales que dificultaron la estrategia diagnóstica. También se discuten las implicancias del diagnóstico para el asesoramiento genético familiar.
Asunto(s)
Trastorno Autístico/genética , Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Discapacidad Intelectual/genética , Adolescente , Preescolar , Humanos , Masculino , FenotipoRESUMEN
The Na+/myo-inositol cotransporter (SMIT1) is overexpressed in human Down syndrome (DS) and in trisomy 16 fetal mice (Ts16), an animal model of the human condition. SMIT1 overexpression determines increased levels of intracellular myo-inositol, a precursor of phophoinositide synthesis. SMIT1 is overexpressed in CTb cells, an immortalized cell line established from the cerebral cortex of a Ts16 mouse fetus. CTb cells exhibit impaired cytosolic Ca2+ signals in response to glutamatergic and cholinergic stimuli (increased amplitude and delayed time-dependent kinetics in the decay post-stimulation), compared to our CNh cell line, derived from the cerebral cortex of a euploid animal. Considering the role of myo-inositol in intracellular signaling, we normalized SMIT1 expression in CTb cells using specific mRNA antisenses. Forty-eight hours post-transfection, SMIT1 levels in CTb cells reached values comparable to those of CNh cells. At this time, decay kinetics of Ca2+ signals induced by either glutamate, nicotine, or muscarine were accelerated in transfected CTb cells, to values similar to those of CNh cells. The amplitude of glutamate-induced cytosolic Ca2+ signals in CTb cells was also normalized. The results suggest that SMIT1 overexpression contributes to abnormal cholinergic and glutamatergic Ca2+ signals in the trisomic condition, and knockdown of DS-related genes in our Ts16-derived cell line could constitute a relevant tool to study DS-related neuronal dysfunction.
Asunto(s)
Corteza Cerebral/metabolismo , Colinérgicos/farmacología , Ácido Glutámico/metabolismo , Simportadores/metabolismo , Acetilcolina/metabolismo , Animales , Línea Celular , Supervivencia Celular , Corteza Cerebral/efectos de los fármacos , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 16/metabolismo , Modelos Animales de Enfermedad , Síndrome de Down/genética , Feto/efectos de los fármacos , Ratones , Mosaicismo , Neuronas/efectos de los fármacos , Nicotina/farmacología , Simportadores/genética , Trisomía/genéticaRESUMEN
Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the introduction of bortezomib (Bzb). The mechanism underlying innate resistance of MM to Bzb is unknown. In the present study, we have investigated how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy (Bzb and carfilzomib). High levels of MAF protein were found in t(14;16) cell lines; cell lines from the t(4;14) subgroup had intermediate levels, whereas cell lines from the other subgroups had low levels. High expression of MAF protein in t(14;16) was associated with significantly higher PI half-maximum inhibitory concentration values compared with other molecular subgroups. PI exposure abrogated glycogen synthase kinase 3ß (GSK3ß)-mediated degradation of MAF protein, resulting in increased MAF protein stability and PI resistance. Subsequent studies using loss-of-function and gain-of-function models showed that silencing MAF led to increased sensitivity to PIs, enhanced apoptosis, and activation of caspase-3, -7, -8, -9, poly (ADP-ribose) polymerase, and lamin A/C. In contrast, overexpression of MAF resulted in increased resistance to PIs and reduced apoptosis. These results define the role of MAF and GSK3 in the resistance of t(14;16) MM to PIs and identifies a novel mechanism by which MAF protein levels are regulated by PIs, which in turn confers resistance to PIs.
Asunto(s)
Resistencia a Antineoplásicos , Inmunidad Innata , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Inhibidores de Proteasoma/uso terapéutico , Proteínas Proto-Oncogénicas c-maf/metabolismo , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 16/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Inmunidad Innata/efectos de los fármacos , Laminas/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pronóstico , Inhibidores de Proteasoma/farmacología , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-maf/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Translocación GenéticaRESUMEN
Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/complicaciones , Trastornos Generalizados del Desarrollo Infantil/genética , Cromosomas Humanos/genética , Variaciones en el Número de Copia de ADN , Epilepsia/complicaciones , Adolescente , Secuencia de Bases , Brasil , Niño , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 22/genética , Femenino , Genómica , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleAsunto(s)
Mutación , Síndrome de Rubinstein-Taybi/genética , Adolescente , Adulto , Secuencia de Bases , Brasil , Proteína de Unión a CREB , Niño , Preescolar , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 2/genética , Codón sin Sentido , Análisis Mutacional de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Mutación Missense , Polimorfismo de Nucleótido Simple , Síndrome de Rubinstein-Taybi/patología , Eliminación de Secuencia , Translocación Genética , Adulto JovenRESUMEN
Chromosome microarray analysis of patients with developmental delay has provided evidence of small deletions or duplications associated with this clinical phenotype. In this context, a 7.1- to 8.7-Mb interstitial deletion of chromosome 16 is well documented, but within this interval a rare 200-kb deletion has recently been defined that appears to be associated with obesity, or developmental delay together with overgrowth. We report a patient carrying this rare deletion, who falls into the latter clinical category, but who also carries a second very rare deletion in 13q31.3. It remains unclear if this maternally inherited deletion acts as a second copy number variation leading to pathogenic variation, or is non-causal and the true modifiers are yet to be determined.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 16/genética , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Preescolar , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
BACKGROUND: Association between DNA alterations and clinical parameters as recurrence, survival or prognosis has been found in a variety of tumors. A clear association between Medullary Thyroid Carcinoma (MTC) and RET oncogene mutation has been accepted. Specifically M918T RET mutation represents the main genetic event in most cases of sporadic MTC (SMTC) and limited chromosomal alterations analyses have been performed. METHODS: In the present work, a comparative genomic hybridization (CGH) study was performed using DNA from a primary tumor in a M918T RET mutation-positive SMTC patient and from its lymph node metastasis to investigate additional genetic alterations. We studied a patient with 15 years of follow-up and persistence of disease, confirmed by periodical elevated serum calcitonin (CT) levels. RESULTS: Only 3 chromosomal imbalances were identified in the primary tumor, gain of 18p, and loss of 6p and 16p region, whereas 25 chromosomal imbalances were identified in the metastasis (9 gains and 16 losses). CONCLUSION: The chromosomal changes 6p-, 16p-, 18p + could determine in part the oncogenic phenotype in the primary M918T RET positive tumor and probably related to persistence of high serum CT levels in this patient. The additional chromosomal changes observed could be related to the metastasis phenotype. We suggest that some genes mapped at 6p, 16p and 18p chromosomal regions, could act as genes associated to cancer and could be related to persistent SMTC and good prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1720753793691097.
Asunto(s)
Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 6/genética , Neoplasias de la Tiroides/genética , Anciano , Carcinoma Neuroendocrino , Hibridación Genómica Comparativa , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Trisomy 16q is a clinically recognizable entity presenting with a wide spectrum of abnormalities. Only five infants with a diagnosis of partial trisomy 16q13 â qter have been previously reported, and all died during the first year of life. We report the clinical and molecular cytogenetic findings in a patient with trisomy 16q13 â qter due to the presence of a supernumerary marker chromosome (SMC). The child presented with microcephaly, ambiguous genitalia, cardiac malformations and dysmorphic features. Cytogenetic investigation using GTG-banding, spectral karyotyping (SKY) and fluorescence in situ hybridization analyses revealed an SMC of maternal origin with karyotype der(15)t(15;16)(q13;q13). Specific genotype-phenotype correlations among different segments of the 16q region cannot yet be defined. We suggest that the involvement of the entire region spanning from 16q11 to 16q22 is necessary for the characteristic phenotype of the trisomy 16q.
Asunto(s)
Anomalías Múltiples/genética , Trisomía/genética , Cromosomas Humanos Par 16/genética , Trastornos del Desarrollo Sexual/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Cariotipo , Masculino , Microcefalia/genética , FenotipoRESUMEN
Chromosome abnormalities detected in metaphases from multiple myeloma (MM) cells have a clear impact on prognosis and response to therapy. Thirteen out of 50 (26%) patients with plasma cell disorders and abnormal karyotypes (11 with MM and 2 with plasma cell leukemia (PCL)) were selected for inclusion in the present report based on the presence of karyotypes with new and/or infrequent structural aberrations. Thirty-three new rearrangements, including a novel recurrent aberration: psu dic(5;1)(q35;q10), were detected. Chromosome 1 was the most frequently involved. Gains of genetic material (57%) were noted more frequently than losses (43%). Three rearrangements that were observed only once in the literature appear to be recurrent from our data: del(16)(q13), del(5)(p13) and i(3)(q10), the latter being a single structural aberration in the karyotype. Clinical parameters from our series were compared with 2 control groups: 20 MM cases with recurrent aberrations in MM/PCL with a similar distribution of abnormalities associated with poor prognosis (group 1), and 40 with normal karyotypes and fluorescence in situ hybridization analysis (group 2). Significantly increased serum calcium levels (p = 0.022) in patients with new and/or infrequent chromosome changes with respect to both control groups, and a higher percentage of bone marrow plasma cell infiltration (p = 0.005), ß(2) microglobulin, and lactate dehydrogenase levels (p < 0.0001) compared to group 2 were observed. Our results suggest that some of these novel rearrangements may be capable to deregulate genetic mechanisms related to the development and/or progression of the disease. The finding of new recurrent aberrations supports this hypothesis.
Asunto(s)
Aberraciones Cromosómicas , Leucemia de Células Plasmáticas/genética , Mieloma Múltiple/genética , Adulto , Anciano , Anciano de 80 o más Años , Calcio/sangre , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 5/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia de Células Plasmáticas/sangre , Leucemia de Células Plasmáticas/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , PronósticoRESUMEN
The 16q21 --> qter duplication is a chromosomal abnormality rarely found in liveborn infants, with only four published cases. We report here on the 7-year follow-up of a female patient with trisomy 16q21 --> qter due to a maternal balanced translocation t(4;16)(q35.2;q21). The patient shows severe mental retardation, congenital heart malformations, nephropathy, and other congenital anomalies. The derivative chromosome was characterized by GTG banding, fluorescent in situ hybridization (FISH) with different BAC probes and the array technique, in order to map the breakpoints. The patient has a 16q21 --> qter duplication, with a 4q35 --> qter monosomy, which we assume does not contribute to the abnormal phenotype. This is the first reported case of postnatal survival to the age of 7 years, an unusually long time in this chromosomal syndrome.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 4/genética , Cardiopatías Congénitas/genética , Discapacidad Intelectual/genética , Trisomía/genética , Anomalías Múltiples/mortalidad , Adulto , Femenino , Estudios de Seguimiento , Cardiopatías Congénitas/mortalidad , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Discapacidad Intelectual/mortalidad , Cariotipificación , Masculino , Monosomía , Tasa de Supervivencia , Translocación GenéticaRESUMEN
OBJECTIVE: To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure. STUDY DESIGN: We resequenced genes from parents whose infants were homozygous for mutations in SFTPB or ABCA3. For infants with only 1 heterozygous parent, we performed microsatellite analysis for chromosomes 2 (SFTPB) and 16 (ABCA3). RESULTS: We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous. For the SP-B-deficient infant, microsatellite markers confirmed maternal heterodisomy with segmental isodisomy. Microsatellite analysis confirmed paternal isodisomy for the 3 ABCA3-deficient infants. Two ABCA3-deficient infants underwent lung transplantation at 3 and 5 months of age, respectively, and 2 infants died. None exhibited any nonpulmonary phenotype. CONCLUSIONS: Uniparental disomy should be suspected in infants with rare homozygous mutations in SFTPB or ABCA3. Confirmation of parental carrier status is important to provide recurrence risk and to monitor expression of other phenotypes that may emerge through reduction to homozygosity of recessive alleles.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Mutación/genética , Proteína B Asociada a Surfactante Pulmonar/deficiencia , Proteína B Asociada a Surfactante Pulmonar/genética , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 2/genética , Resultado Fatal , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
OBJECTIVE: The etiology of otosclerosis is poorly understood and environmental as well as genetic factors have been implicated. In this paper we will present 3 cases of otosclerosis with a clinical history of trauma and we will discuss with a literature review the place of trauma in otosclerosis etiology. CLINICAL CASES: 3 patients with clinically diagnosed otosclerosis, operated, and with a clinical history of previous head trauma. DISCUSSION AND CONCLUSION: It is probable that environmental factors could be involved in the development of the disease and we think that trauma could be one of them. The mechanisms by which it could results in otosclerosis remain unknown. However these cases appear to be rare and under studied.
Asunto(s)
Oído/lesiones , Procedimientos Quirúrgicos Otológicos/métodos , Otosclerosis/etiología , Adulto , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 7/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Otosclerosis/genética , Factores de Riesgo , Heridas y Lesiones/complicacionesRESUMEN
Non-syndromic cleft lip with or without cleft palate (NSCLP) results from the complex interaction between genes and environmental factors. Candidate gene analysis and genome scans have been employed to identify the genes contributing to NSCLP. In this study, we evaluated the 16q24.1 chromosomal region, which has been identified by multiple genome scans as an NSCLP region of interest. Two candidate genes were found in the region: interferon regulatory factor 8 (IRF8) and cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2). Initially, Caucasian and Hispanic NSCLP multiplex families and simplex parent-child trios were genotyped for single nucleotide polymorphisms (SNPs) in both IRF8 and CRISPLD2. CRISPLD2 was subsequently genotyped in a data set comprised of NSCLP families from Colombia, South America. Linkage disequilibrium analysis identified a significant association between CRISPLD2 and NSCLP in both our Caucasian and Hispanic NSCLP cohorts. SNP rs1546124 and haplotypes between rs1546124 and either rs4783099 or rs16974880 were significant in the Caucasian multiplex population (P=0.01, P=0.002 and P=0.001, respectively). An altered transmission of CRISPLD2 SNPs rs8061351 (P=0.02) and rs2326398 (P=0.06) was detected in the Hispanic population. No association was found between CRISPLD2 and our Colombian population or IRF8 and NSCLP. In situ hybridization showed that CRISPLD2 is expressed in the mandible, palate and nasopharynx regions during craniofacial development at E13.5-E17.5, respectively. Altogether, these data suggest that genetic variation in CRISPLD2 has a role in the etiology of NSCLP.