RESUMEN
The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case-by-case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell-free DNA.
Asunto(s)
Trastornos de los Cromosomas/etiología , Diagnóstico Preimplantación/métodos , Muestra de la Vellosidad Coriónica/métodos , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/embriología , Femenino , Humanos , Mosaicismo/embriología , EmbarazoRESUMEN
BACKGROUND: Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. METHODS: Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. RESULTS: We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. LIMITATIONS: The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background. CONCLUSION: These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
Asunto(s)
Trastorno Autístico/etiología , Trastorno Autístico/metabolismo , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/metabolismo , Discapacidad Intelectual/etiología , Discapacidad Intelectual/metabolismo , Aprendizaje , Memoria , Transducción de Señal/efectos de los fármacos , Complejos de Ubiquitina-Proteína Ligasa/deficiencia , Proteína de Unión al GTP rhoA/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Alelos , Animales , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 16/metabolismo , Cognición , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Ratones , Ratones Noqueados , Fenotipo , Resultado del Tratamiento , Quinasas Asociadas a rho/metabolismoRESUMEN
BACKGROUND: Cat eye syndrome (CES) is a rare chromosomal disorder with a known incidence of 1 per 50,000-150,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients. In addition, other ocular malformations and systemic defects can be present. The aim of this report is to present a patient with unilateral iris coloboma related to a mosaicism of cat eye syndrome. METHODS: A complete ophthalmological and systemic evaluation was performed in a three-year-old male. He also underwent a standard karyotype and FISH analysis with a probe against the 22q11.2 locus. RESULTS: The ophthalmological and systemic evaluation revealed a unilateral iris coloboma and ipsilateral auricular malformations. Karyotype analysis of blood leukocytes indicated the presence of a marker chromosome in 6% of the analyzed cells. FISH analysis showed three positive signals in 5.5% of the analyzed nucleus. CONCLUSION: This patient presented two of the three classic manifestations of CES; interestingly, they were unilateral. The 22q11 duplication was identified by standard karyotype and confirmed with FISH. The present case demonstrates the importance of conducting a multidisciplinary approach in patients with congenital malformations associated with known syndromes.
Asunto(s)
Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 22/genética , Coloboma/complicaciones , Anomalías del Ojo/patología , Enfermedades del Iris/complicaciones , Mosaicismo , Fenotipo , Aneuploidia , Preescolar , Trastornos de los Cromosomas/etiología , Anomalías del Ojo/etiología , Marcadores Genéticos , Humanos , Cariotipificación , MasculinoRESUMEN
The birth prevalence of each common autosomal trisomy (21, 18 and 13) increases with advancing maternal age and this is the most important epidemiological risk factor. Prevalence during pregnancy is also dependent on gestational age. Other factors claimed to influence prevalence include paternal age, ethnicity, family history, premature reproductive aging, parity, twinning, smoking, environmental exposures, maternal medical conditions, and predispositions. We review the evidence for these associations since they may provide insights into causal mechanisms. When investigating potential co-factors it is important to adequately allow for maternal age and minimize its confounding contribution. This is well illustrated by reports of an inverse paternal age effect where there is strong correlation between parental ages. Gestational age at diagnosis, availability of prenatal screening, diagnostic testing, and elective termination of affected pregnancies and healthcare disparities also confound the studies on ethnicity, medical conditions, and predispositions or environmental factors. Data from twin zygosity studies demonstrate the importance of differences in fetal viability for affected pregnancies. We conclude that existing epidemiological evidence for most of the co-factors discussed should currently be considered tenuous; history of Down syndrome, albeit biased, may be an exception. The co-factors may yet provide clues to hitherto poorly understood causal pathways.
Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/etiología , Adulto , Trastornos de los Cromosomas/epidemiología , Femenino , Edad Gestacional , Humanos , Paridad/genética , Paridad/fisiología , Embarazo , Prevalencia , Grupos Raciales/genética , Grupos Raciales/estadística & datos numéricosRESUMEN
BACKGROUND: The implementation of molecular karyotyping has resulted in an improved diagnostic yield in the genetic diagnostics of congenital anomalies, detected prenatally or after the termination of pregnancy. However, the systematic epidemiologic ascertainment of copy number variations in the etiology of congenital anomalies has not yet been sufficiently explored. METHODS: Consecutive fetuses, altogether 204, with major single or multiple congenital anomalies were ascertained by using the SLOCAT registry for the period from 2011 to 2015. After excluding aneuploidies by using conventional karyotyping or Quantitative Fluorescence-Polymerase Chain Reaction, array comparative genomic hybridization was performed for the detection of copy number variations. RESULTS: We identified pathogenic or likely pathogenic copy number variations in 14 fetuses (6.8%); 2.9% in fetuses with isolated, and 3.9% in fetuses with multiple congenital anomalies. Additionally, aneuploidies and major structural chromosomal abnormalities were detected in 40.2%. CONCLUSION: Our systematic approach of ascertaining congenital anomalies resulted in explaining the etiology of congenital anomalies in 47% of fetuses after the termination of pregnancy. By using array comparative genomic hybridization, we found that copy number variations represent an important part in the etiology of multiple, as well as isolated congenital anomalies, which indicates the importance of analyzing copy number variations in the diagnostic approach of fetuses with congenital anomalies after the termination of pregnancy.
Asunto(s)
Anomalías Congénitas/etiología , Anomalías Congénitas/genética , Variaciones en el Número de Copia de ADN/genética , Anomalías Múltiples/genética , Aneuploidia , Aberraciones Cromosómicas/embriología , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Estudios de Cohortes , Hibridación Genómica Comparativa/métodos , Femenino , Feto , Humanos , Cariotipificación/métodos , Masculino , Embarazo , Diagnóstico Prenatal/métodosRESUMEN
PURPOSE: To determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either maternal or paternal origin. METHODS: We implemented a systematic review of scholarly literature followed by comprehensive meta-analysis to quantitatively synthesize data from reports relating to use of ART to occurrence of any imprinting disorder of humans, including Beckwith-Wiedemann (BWS), Angelman (AS), Prader-Willi (PWS), and Silver-Russell (SRS) syndromes, as well as transient neonatal diabetes mellitus (TNDB) and sporadic retinoblasoma (RB). RESULTS: The systematic review identified 13 reports presenting unique data from 23 studies that related conception following ART to occurrence of imprinting disorders. Multiple studies of four disorder were identified, for which meta-analysis yielded the following summary estimates of associations with a history of ART: AS, summary odds ratio (sOR) = 4.7 (95% confidence interval (CI) 2.6-8.5, 4 studies); BWS, sOR = 5.8 (95% CI 3.1-11.1, 8 studies); PWS, sOR = 2.2 (95% CI 1.6-3.0, 6 studies); SRS, sOR = 11.3 (95% CI 4.5-28.5, 3 studies). Only one study reported on each of TNDB and RB. CONCLUSION: Published data reveal positive associations between history of ART conception and each of four imprinting disorders. Reasons for these associations warrant further investigation.
Asunto(s)
Trastornos de los Cromosomas/etiología , Fertilización , Impresión Genómica , Técnicas Reproductivas Asistidas/efectos adversos , Femenino , Humanos , Factores de RiesgoRESUMEN
Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.
Asunto(s)
Apoptosis/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Aberraciones Cromosómicas/efectos de la radiación , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Mesenquimatosas/efectos de la radiación , Traumatismos por Radiación/patología , Irradiación Corporal Total/efectos adversos , Adulto , Células Madre Adultas/efectos de la radiación , Células de la Médula Ósea/citología , Células de la Médula Ósea/patología , Diferenciación Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Células Cultivadas , China , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/patología , Femenino , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/patología , Hospitales Universitarios , Humanos , Leucemia/patología , Leucemia/terapia , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/patología , Necrosis , Traumatismos por Radiación/etiología , Acondicionamiento Pretrasplante/efectos adversos , Células Tumorales Cultivadas , Adulto JovenRESUMEN
The aim of this study was to examine the clinical and cytogenetic results of 4761 amniocentesis (AS) cases retrospectively in our clinic in southeast China. The prenatal diagnosis indications, detected chromosomal anomalies and the detection rate of chromosomal abnormalities were studied in 4761 patients who underwent AS between June 2014 and July 2016 retrospectively. Chromosomal abnormality was detected in 137 (2.88%) of the 4761 samples (89.1% numerical, 10.9% structural). The most frequent numerical chromosomal abnormality was trisomy 21 (59.0%). Clinically insignificant polymorphisms were the most frequent structural changes (n = 284). In our study, the frequency and proportion of abnormal karyotypes varied substantially across different maternal AS indications. Impact statement What is already known on this subject: Several studies on amniocentesis indications and results have been reported from China and from other countries. It has been known that the most common indications were the increased risk at maternal serum screenings (MSS) and advanced maternal age (AMA). What the results of this study add: In our study we make a conclusion that the indications and results of AS cases from our centre indicated the significance of genetic screening. What the implications are of these findings for clinical practice and/or further research: Our data could offer informative data for proper prenatal genetic counselling of pregnant women and their partners in Wuxi, China.
Asunto(s)
Amniocentesis/estadística & datos numéricos , Trastornos de los Cromosomas/epidemiología , Adulto , China/epidemiología , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/etiología , Femenino , Humanos , Cariotipificación/métodos , Cariotipificación/estadística & datos numéricos , Edad Materna , Embarazo , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
La miocardiopatía no compa da (MNC) es una enf medad congénita caracterizada por la ausencia de compaqctación del miocardio ventricular. Tiene una gran variabilidad genética, clinica, evolutiva y pronóstica. Presentamos a una recién nacida pretérmino (34 semanas) con restrición del crecimiento intrauterino, fenotipo peculiar, hipotonia generalizada y distrés respiratono. La ecocardiografía objetiva ausencia de compactación del ventrículo izquierdo y disfunción sistólica leve, que se trata con captopril y ácido acetilsalicílico. Desarrolla crisis convulsivas parciales resistentes al tratamiento y se evidencia ausencia de respuesta en potenciales auditivo-visuales del tronco del encéfalo. El cariotipo convencional es normal pero el estudio de microarrays revela deleción 1p36.33-p36.23. El estudio carddiológico y genético de los progenitores es normal. El conocimiento de esta cardiopatía permite un diagnóstico precoz. Debe realizarse despistaje a familiares de primer grado. Dada la frecuente asociación entre MNC y síndrome 1p36 recomendamos incluir estudio genético mediante microarrays en pacientes con sospecha de asociación sindrómica y normalidad en el cariotipo convencional, como en el caso que presentamos (AU)
The non-compaction cardiomypathy (MNC) is a congenital disorder characterized by the absence of the compaction ventricular myocardium. It presents a high variability, genetic, clinical, evolutionary and prognostic. We report a preterm newborn (34 weeks) with intrauterine growth restriction particular phenotype, generalized hypotonia and respiratory distress. Echocardiography objective absence of compaction left ventricular myocardium and mild sistolic dysfunction, treated with captopril and acetylsalicylic acid. Develops resistant treatment partial seizurcs and lack response evident in visual-auditory evoked potentials brainstem. The conventional kariotype is normal but the microarray study revealed 1p.36-p36.23 deletion. Cardiological and genetic study of the parents are normal. Thebest knowledge of the MNC allows earlier diagnosis. Have to perform screening for first-degree relatives. Given the frequent association between MNC and lp36 syndrome, we recommend using microarray genetic study in patients with suspected syndromic association and normality in the conventional as in the case presented (AU)
Asunto(s)
Humanos , Femenino , Recién Nacido , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico por imagen , Trastornos de los Cromosomas/etiología , Deleción Cromosómica , Monosomía/diagnóstico , Cardiomiopatías/genética , Eliminación de Gen , Trastornos de los Cromosomas/genética , Ecocardiografía/métodosRESUMEN
INTRODUCTION: Intracytoplasmic sperm injection (ICSI) currently helps many couples with male infertility. However, ICSI procedure may cause asynchronous sperm decondensation. This could introduce a risk for aneuploidy. The ICSI technique also could cause damage to the second meiotic spindle during injection and cause significantly abnormal pairing of chromosomes when compared with In vitro fertilization (IVF). In this study, we have examined whether ICSI has a higher incidence of aneuploidy when compared with IVF. MATERIAL AND METHODS: A retrospective study was conducted on 36 individuals. Common numbers of chromosome abnormalities were detected using fluorescent in-situ hybridization (FISH). Seven probes were used to detect chromosome X, Y, 13, 16, 18, 21, and 22. Chi-square test was used for statistical analysis and presented as odd ratios with confidence intervals. RESULTS: The age range was 26 through 44 (mean age 35.5) for IVF and 25 through 46 (mean age 35.8) for ICSI. From the 36 egg retrievals, 57 embryos were obtained from nine individuals using IVF and 183 embryos were obtained from 27 individuals using ICSI. For the IVF group, 37 of the 57 examined embryos were abnormal (65%), whereas 128 of 183 examined embryos were abnormal for the ICSI group (69.9%). Among the 57 embryos from the IVF cases, the number of absolute abnormal chromosomes were as follows: X&Y chromosomes: 4 (12.9%), chromosome 13: 9 (29%), chromosome 16: 7 (22.5%), chromosome 18: 6 (19.3%), chromosome 21: 8 (25.8%), chromosome 22: 10 (32.2%). For the ICSI embryos: X and Y chromosomes: 18 (14%), chromosome 13: 34 (26.5%), chromosome 16: 23 (18%), chromosome 18: 23 (18%), chromosome 21: 26 (20.3%), chromosome 22: 31 (24.2%). The odds ratios for the difference between IVF and ICSI for each chromosome were as follows: X&Y chromosomes: 1.53 (0.598-3.916), chromosome 13: 0.969 (0.443-2.122), chromosome 16: 0.709 (0.307-1.639), chromosome 18: 1.650 (0.650-4.188), chromosome 21: 0.777 (0.350-1.724), chromosome 22: 0.647 (0.311-1.348). Overall no significant difference between two insemination procedures was seen 0.948 (0.678-1.324). CONCLUSIONS: As a result; ICSI does not create a significantly higher aneuploidy number when compared with IVF as examined by FISH analysis of seven chromosome pairs.
Asunto(s)
Aneuploidia , Aberraciones Cromosómicas/estadística & datos numéricos , Trastornos de los Cromosomas/etiología , Cromosomas Humanos , Inyecciones de Esperma Intracitoplasmáticas/efectos adversos , Adulto , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 22 , Cromosomas Humanos X , Cromosomas Humanos Y , Femenino , Fertilización In Vitro/efectos adversos , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Chromosome deletions and duplications-copy number variations (CNVs)-are a major contribution to the genome variability and can be either pathogenic or not. A particular class, the microdeletions and microduplications, which alter <5 Mb, have been extensively associated with developmental delay and intellectual disability. Although their prevalence in pregnancies and newborn is relatively low, their estimates in preimplantation embryos are poorly defined. The introduction of novel technologies for preimplantation genetic diagnosis of aneuploidies (PGD-A) caused new possibilities and challenges associated with diagnosis of subchromosomal CNVs. Both technical aspects of performing genomewide microarray or next generation sequencing analysis on single cells and interpretation issues are subject of debate. The latter include the reliability of detection of CNVs from embryonic biopsies, their clinical classification based on reproductive outcomes, as well as how before and after test counseling should be organized. It is also important to consider that the current resolution of these technologies from single cells is usually >10 Mb, thus ruling out the possibility to diagnose the most important recurrent microdeletion and microduplication syndromes. Furthermore, at present we face with a lack of well-designed studies addressing the actual resolution and accuracy of CNVs detection in PGD-A and no reference databases is available to evaluate their pathogenicity. Accordingly, it seems reasonable at the moment to avoid the reporting of subchromosomal CNVs in PGD-A. However, although these issues require proper handling, they should not lead us away from providing an improved preimplantation genetic diagnosis.
Asunto(s)
Blastocisto/patología , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/prevención & control , Duplicación Cromosómica , Cromosomas Humanos , Pruebas Genéticas , Diagnóstico Preimplantación/métodos , Técnicas Reproductivas Asistidas/efectos adversos , Aneuploidia , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Medición de Riesgo , Factores de RiesgoRESUMEN
The application of next generation sequencing platforms for embryonic aneuploidy screening provides enhanced resolution that allows routine evaluation of subchromosomal copy number abnormalities and mosaicism. Approximately 20% of embryos that would be designated as euploid using the conventional 24-chromosome aneuploidy screening will have evidence of a subchromosomal abnormality or mosaicism. This new information brings many challenges. Understanding the impact of these abnormalities on implantation and delivery rates is key to optimizing clinical counseling and management.
Asunto(s)
Aneuploidia , Blastocisto/patología , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos , Pruebas Genéticas , Mosaicismo , Diagnóstico Preimplantación/métodos , Técnicas Reproductivas Asistidas/efectos adversos , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE: To establish the value of array comparative genomic hybridization (CGH) for preimplantation genetic diagnosis (PGD) in embryos of translocation carriers in combination with vitrification and frozen embryo transfer in nonstimulated cycles. DESIGN: Retrospective data analysis study. SETTING: Academic centers for reproductive medicine and genetics. PATIENT(S): Thirty-four couples undergoing PGD for chromosomal rearrangements from October 2013 to December 2015. INTERVENTION(S): Trophectoderm biopsy at day 5 or day 6 of embryo development and subsequently whole genome amplification and array CGH were performed. MAIN OUTCOME MEASURE(S): This approach revealed a high occurrence of aneuploidies and structural rearrangements unrelated to the parental rearrangement. Nevertheless, we observed a benefit in pregnancy rates of these couples. RESULT(S): We detected chromosomal abnormalities in 133/207 embryos (64.2% of successfully amplified), and 74 showed a normal microarray profile (35.7%). In 48 of the 133 abnormal embryos (36.1%), an unbalanced rearrangement originating from the parental translocation was identified. Interestingly, 34.6% of the abnormal embryos (46/133) harbored chromosome rearrangements that were not directly linked to the parental translocation in question. We also detected a combination of unbalanced parental-derived rearrangements and aneuploidies in 27 of the 133 abnormal embryos (20.3%). CONCLUSION(S): The use of trophectoderm biopsy at the blastocyst stage is less detrimental to the survival of the embryo and leads to a more reliable estimate of the genomic content of the embryo than cleavage-stage biopsy. In this small cohort PGD study, we describe the successful implementation of array CGH analysis of blastocysts in patients with a chromosomal rearrangement to identify euploid embryos for transfer.
Asunto(s)
Blastocisto/patología , Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos , Hibridación Genómica Comparativa , Fertilización In Vitro/efectos adversos , Reordenamiento Génico , Pruebas Genéticas , Diagnóstico Preimplantación/métodos , Biopsia , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Criopreservación , Técnicas de Cultivo de Embriones , Transferencia de Embrión , Femenino , Predisposición Genética a la Enfermedad , Humanos , Nacimiento Vivo , Fenotipo , Ploidias , Valor Predictivo de las Pruebas , Embarazo , Índice de Embarazo , Estudios Retrospectivos , Resultado del Tratamiento , VitrificaciónRESUMEN
Chromosomal rearrangements have long been known to significantly impact fertility and miscarriage risk. Advancements in molecular diagnostics are challenging contemporary clinicians and patients in accurately characterizing the reproductive risk of a given abnormality. Initial attempts at preimplantation genetic diagnosis were limited by the inability to simultaneously evaluate aneuploidy and missed up to 70% of aneuploidy in chromosomes unrelated to the rearrangement. Contemporary platforms are more accurate and less susceptible to technical errors. These techniques also offer the ability to improve outcomes through diagnosis of uniparental disomy and may soon be able to consistently distinguish between normal and balanced translocation karyotypes. Although an accurate projection of the anticipated number of unbalanced embryos is not possible at present, confirmation of normal/balanced status results in high pregnancy rates (PRs) and diagnostic accuracy.
Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Inversión Cromosómica , Cromosomas Humanos , Reordenamiento Génico , Pruebas Genéticas , Diagnóstico Preimplantación/métodos , Técnicas Reproductivas Asistidas/efectos adversos , Translocación Genética , Blastocisto/patología , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Transferencia de Embrión , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Embryonic mosaicism occurs when two or more cell populations with different genotypes are present within the same embryo. New diagnostic techniques for preimplantation genetic screening (PGS), such as next-generation sequencing, have led to increased reporting of mosaicism. The interpretation of mosaicism is complicated because the transfer of some mosaic embryos has resulted in live births. Mosaic embryos may represent a third category between normal (euploidy) and abnormal (aneuploidy). This category of mosaic embryos may be characterized by decreased implantation and pregnancy potential as well as increased risk of genetic abnormalities and adverse pregnancy outcomes. Euploid embryos should be preferentially transferred over mosaic embryos. Genetic counseling is necessary before the transfer of a mosaic embryo is considered. Certain types of mosaic embryos should be preferentially transferred over others. Transfer of embryos with mosaic trisomies 2, 7, 13, 14, 15, 16, 18, and 21 may pose the most risk of having a child affected with a trisomy syndrome; however, the transfer of embryos with mosaic monosomies or other mosaic trisomies are not devoid of risk. Patients must be counseled about the risk of undetected monosomies or trisomies within a biopsy specimen as well as the risk of intrauterine fetal demise or uniparental disomy with the transfer of mosaic embryos. Until more data are available, patients should be encouraged to undergo another cycle to obtain euploid embryos, when possible, rather than transferring a mosaic embryo.
Asunto(s)
Blastocisto/patología , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/prevención & control , Cromosomas Humanos , Pruebas Genéticas , Mosaicismo , Diagnóstico Preimplantación/métodos , Técnicas Reproductivas Asistidas/efectos adversos , Aneuploidia , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Transferencia de Embrión , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Whole-chromosome aneuploidy screening has become a common practice to improve outcomes and decrease embryonic transfer order in patients undergoing treatment for infertility through in vitro fertilization. Despite implementation of this powerful technology, a significant percentage of euploid embryos fail to result in successful deliveries. As technology has evolved, detection of subchromosomal imbalances and embryonic mosaicism has become possible, and these serve as potential explanations for euploid embryo transfer failures. Cases involving a parent with a balanced translocation provide a unique opportunity to characterize the capabilities and limitations of detecting segmental imbalances with a variety chromosome screening platforms. Adaptation of these methods to de novo imbalances now represent an ongoing challenge in the field of preimplantation genetic screening as additional factors including mosaicism, clinical predictive value, and distinguishing true imbalances from technical artifacts must be more carefully considered.
Asunto(s)
Aneuploidia , Blastocisto/patología , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos , Pruebas Genéticas , Mosaicismo , Diagnóstico Preimplantación/métodos , Técnicas Reproductivas Asistidas/efectos adversos , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Hibridación Genómica Comparativa , Transferencia de Embrión , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.
Asunto(s)
Anomalías Múltiples/etiología , Proteínas Portadoras/genética , Trastornos de los Cromosomas/etiología , Discapacidades del Desarrollo/etiología , Haploinsuficiencia/genética , Mutación/genética , Animales , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1 , Femenino , Humanos , Lactante , Masculino , Ratones , Fenotipo , PronósticoRESUMEN
OBJETIVO: Describir la tendencia y la distribución de las anomalías congénitas (AC) cromosómicas en la Comunitat Valenciana, en menores de un año, durante el periodo 2007-2011. METODOLOGÍA: Se seleccionó a los nacidos vivos y muertos e interrupciones voluntarias del embarazo por AC entre 2007 y 2011 del Registro Poblacional de AC de la Comunitat Valenciana con AC cromosómica (códigos Q90-Q99.9 de la 10.ª Clasificación Internacional de Enfermedades-British Pediatric Asociation). Se calcularon la prevalencia por 10.000 nacidos y sus intervalos de confianza (IC) al 95% para el conjunto de AC cromosómica y algunos síndromes cromosómicos. El análisis se realizó mediante el cálculo de prevalencia y se compararon los datos utilizando la prueba de la chi al cuadrado de Pearson. RESULTADOS: Se identificaron 895 casos de AC cromosómicas, lo que supuso una prevalencia de 33,5 por 10.000 nacimientos (IC del 95%, 31,0-35,9), siendo los síndromes más frecuentes: Down, Edwards, Patau, Turner y Klinefelter. Las prevalencias de las AC cromosómicas y síndrome de Down fueron estables en el periodo, excepto en 2010. El Down fue la AC cromosómica más frecuente (67%) y las interrupciones voluntarias del embarazo por AC, el tipo de finalización del embarazo mayoritario (69%). Entre las AC asociadas, las cardiopatías congénitas representaban un 70,3%. La mayoría de las madres de niños con AC cromosómicas eran españolas (73,3%) y en el grupo de edad de madres mayores de 39 años se identificó la prevalencia más elevada (133,0 por 10.000 nacimientos). La provincia de Castellón presentó la prevalencia más elevada, 39,1 por 10.000 nacimientos. CONCLUSIONES: La prevalencia se ha mantenido estable durante el quinquenio, exceptuando el descenso significativo del año 2010, detectado para AC cromosómicas y 2 de los principales síndromes. Las AC cromosómicas son un importante problema de salud pública, ya que representan el 15% de todas las AC identificadas en la Comunitat Valenciana, coincidiendo con los valores de Europa
OBJECTIVE: To describe the temporal trend and distribution of chromosomal congenital abnormalities (CA) in the Valencia Region, in less than one year olds, during the period 2007-2011. METHODOLOGY: Live births, still births and termination of pregnancy due to foetal anomaly between 2007 and 2011 with chromosomal CA (Q90-Q99.9 codes of the 10th International Classification of Diseases -British Paediatric Association) were selected from the CA population-based Registry of Valencia Region The prevalence per 10,000 births for the chromosomal CA and for the different types of chromosomal syndromes with 95% confidence intervals was calculated. The analysis was performed by calculating prevalences and data were compared using Pearson Chi-squared test. RESULTS: A total of 895 cases were found, representing a prevalence of 33.5 per 10,000 births (95% CI: 31.0-35.9), highlighting five syndromes: Down's, Edward's, Patau, Turner and Klinefelter. The prevalence of chromosomal CA and Down's syndrome were stable over the period, except in 2010. Down's was the most frequent chromosomal CA (67% of the cases), and the most frequent termination of pregnancy type was for foetal anomaly (69%). Cardiac heart defects represented 70.3% of the associated congenital anomalies. Mothers of children with chromosomal CA were mainly Spanish (73.3%). The age group of mothers over 39 years had a higher prevalence (133.0 per 10,000 births). The province of Castellón had the highest prevalence, 39.1 per 10,000 births. CONCLUSIONS: The prevalence has remained stable over the five years, excluding the significant decline in 2010, for chromosomal CA detected and two of the major syndromes. The chromosomal CA are an important public health problem as they represent 15% of all CA identified in the Valencia Region, and agrees with the European data
Asunto(s)
Humanos , Masculino , Femenino , Embarazo , Recién Nacido , Lactante , Anomalías Congénitas/etiología , Anomalías Congénitas/genética , Anomalías Congénitas/mortalidad , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/terapia , Síndrome de Down/epidemiología , Síndrome de Down/prevención & control , Diagnóstico Precoz , Monitoreo Epidemiológico/tendencias , Monitoreo Epidemiológico , Estudios Epidemiológicos , España/epidemiologíaRESUMEN
BACKGROUND: The deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typically results in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit and dysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance. METHODS AND RESULTS: We investigated a large Indian five-generation pedigree with ten affected family members in which chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication in three individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentation of WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1 duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or 4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features. CONCLUSION: We present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.
Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 4 , Trastornos de los Cromosomas/etiología , Discapacidades del Desarrollo/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , India , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Eliminación de Secuencia , Trisomía , Síndrome de Wolf-Hirschhorn/genéticaRESUMEN
PURPOSE: The purpose of this study was to determine whether radiation treatment induces chromosomal aberrations in uveal melanoma (UM) and to evaluate which tumor features determine success of karyotyping and FISH. METHODS: Material from 327 UM-containing enucleated eyes was submitted for karyotyping, while FISH for chromosome 3 was performed in 248 samples. Thirty-six UMs had previously undergone irradiation. Karyotypes were analyzed, and the success rate of karyotyping/FISH was evaluated and compared with clinicopathologic tumor characteristics and prior irradiation. RESULTS: Aberrations were observed in all chromosomes, with chromosomes 1, 3, 6, 8, 13, 15, 16, and Y being altered in at least 15% of the tumors. Aberrations were more common and more complex in previously irradiated tumors (significant for chromosomes 5 [P = 0.004] and 13 [P = 0.04]). Karyotyping and FISH failed significantly more often in irradiated tumors (both P < 0.001). In nonirradiated cases, successful karyotyping was related to a large tumor prominence (P = 0.004) and a high mitotic count (P = 0.007). The success of FISH in these tumors was not associated with any of the studied parameters. In irradiated tumors, karyotyping succeeded more frequently in cases with a high mitotic count (P = 0.03), whereas FISH was more often successful in tumors with a high mitotic count (P = 0.001), a large diameter (P = 0.009) and large prominence (P = 0.008). CONCLUSIONS: Karyotyping and FISH are more often successful in UMs with features characteristic of high tumor aggressiveness, whereas prior irradiation leads to multiple chromosome aberrations and to unsuccessful tests. It will be interesting to determine whether other techniques can provide reliable information on the chromosome status of previously irradiated UMs.