RESUMEN

BACKGROUND: Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. METHODS: We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. RESULTS: Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. CONCLUSIONS: The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.

Asunto(s)

Discapacidad Intelectual , Complejo Mediador , Humanos , Discapacidad Intelectual/genética , Complejo Mediador/genética , Fenotipo

RESUMEN

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

Asunto(s)

Trastorno del Espectro Autista , Células Madre Pluripotentes Inducidas , Trastorno del Espectro Autista/genética , Humanos , Neuronas , Proteómica , Transcriptoma/genética

RESUMEN

BACKGROUND: Wilms tumor (WT) has a not completely elucidated pathogenesis. DNA copy number alterations (CNAs) are common in cancer, and often define key pathogenic events. The aim of this work was to investigate CNAs in order to disclose new candidate genes for Wilms tumorigenesis. RESULTS: Array-CGH of 50 primary WTs without pre-chemotherapy revealed a few recurrent CNAs not previously reported, such as 7q and 20q gains, and 7p loss. Genomic amplifications were exclusively detected in 3 cases of WTs that later relapsed, which also exhibited an increased frequency of gains affecting a 16.2 Mb 1q21.1-q23.2 region, losses at 11p, 11q distal, and 16q, and WT1 deletions. Conversely, aneuploidies of chromosomes 13 and 19 were found only in WTs without further relapse. The 1q21.1-q23.2 gain associated with WT relapse harbours genes such as CHD1L, CRABP2, GJA8, MEX3A and MLLT11 that were found to be over-expressed in WTs. In addition, down-regulation of genes encompassed by focal deletions highlighted new potential tumor suppressors such as CNKSR1, MAN1C1, PAQR7 (1p36), TWIST1, SOSTDC1 (7p14.1-p12.2), BBOX and FIBIN (11p13), and PLCG2 (16q). CONCLUSION: This study confirmed the presence of CNAs previously related to WT and characterized new CNAs found only in few cases. The later were found in higher frequency in relapsed cases, suggesting that they could be associated with WT progression.

RESUMEN

Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment.

RESUMEN

We report on a patient carrying a 17q21.31 microdeletion and exhibiting many common syndrome features, together with other clinical signs which have rarely or never been described to date. The detected 695-kb 17q21.31 deletion is larger than in most previously reported cases but is still probably the result of recombination between flanking low-copy repeats. Due to the complexity of the patient's clinical condition, together with the presence of 3 previously unreported symptoms, namely chronic anemia, cervical vertebrae arthrosis and vertebrae fusion, this case is an important addition to the existing knowledge about the 17q21.31 microdeletion syndrome.

Asunto(s)

Anomalías Múltiples/genética , Anomalías Múltiples/patología , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Genes Dominantes/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Niño , Preescolar , Rotura Cromosómica , Femenino , Humanos , Lactante , Masculino , Radiografía , Síndrome

RESUMEN

The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.

Asunto(s)

Inestabilidad Cromosómica/genética , Pérdida Auditiva/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Humanos , Masculino , Síndrome

RESUMEN

Chromosome microdeletions or duplications are detected in 10-20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of approximately 180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (approximately 1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Genes Supresores de Tumor , Discapacidad Intelectual/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Proteínas Reguladoras de la Apoptosis , Proteínas de Ciclo Celular , Niño , Preescolar , Mapeo Cromosómico , Hibridación Genómica Comparativa , Homólogo 4 de la Proteína Discs Large , Femenino , Dosificación de Gen , Genes p53 , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Fenotipo , Canales de Potasio/genética , Transferasas

RESUMEN

We present the first comprehensive study, to our knowledge, on genomic chromosomal analysis in syndromic craniosynostosis. In total, 45 patients with craniosynostotic disorders were screened with a variety of methods including conventional karyotype, microsatellite segregation analysis, subtelomeric multiplex ligation-dependent probe amplification) and whole-genome array-based comparative genome hybridisation. Causative abnormalities were present in 42.2% (19/45) of the samples, and 27.8% (10/36) of the patients with normal conventional karyotype carried submicroscopic imbalances. Our results include a wide variety of imbalances and point to novel chromosomal regions associated with craniosynostosis. The high incidence of pure duplications or trisomies suggests that these are important mechanisms in craniosynostosis, particularly in cases involving the metopic suture.

Asunto(s)

Aberraciones Cromosómicas , Segregación Cromosómica , Craneosinostosis/genética , Repeticiones de Microsatélite , Humanos , Cariotipificación , Hibridación de Ácido Nucleico/métodos , Polimorfismo Genético

RESUMEN

BACKGROUND: Aplasia of the müllerian ducts leads to absence of the uterine corpus, uterine cervix, and upper (superior) vagina. Patients with müllerian aplasia (MA) often exhibit additional clinical features such as renal, vertebral and cardiac defects. A number of different syndromes have been associated with MA, and in most cases its aetiology remains poorly understood. OBJECTIVE AND METHODS: 14 syndromic patients with MA and 46,XX G-banded karyotype were screened for DNA copy number changes by approximately 1 Mb whole genome bacterial artificial chromosome (BAC) array based comparative genomic hybridisation (CGH). The detected alterations were validated by an independent method and further mapped by high resolution oligo-arrays. RESULTS: Submicroscopic genomic imbalances affecting the 1q21.1, 17q12, 22q11.21, and Xq21.31 chromosome regions were detected in four probands. Presence of the alterations in the normal mother of one patient suggests incomplete penetrance and/or variable expressivity. CONCLUSION: 4 of the 14 patients (29%) were found to have cryptic genomic alterations. The imbalances on 22q11.21 support recent findings by us and others that alterations in this chromosome region may result in impairment of müllerian duct development. The remaining imbalances indicate involvement of previously unknown chromosome regions in MA, and point specifically to LHX1 and KLHL4 as candidate genes.

Asunto(s)

Anomalías Múltiples/genética , Desequilibrio Alélico , Aberraciones Cromosómicas , Genitales Femeninos/anomalías , Conductos Paramesonéfricos/anomalías , Adolescente , Adulto , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos X/genética , Proteínas del Citoesqueleto/genética , Femenino , Dosificación de Gen , Proteínas de Homeodominio/genética , Humanos , Proteínas con Homeodominio LIM , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Síndrome , Factores de Transcripción , Útero/anomalías , Vagina/anomalías , Proteínas Wnt/genética , Proteína Wnt4

RESUMEN

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1-->q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.

Asunto(s)

Enfermedades Genéticas Congénitas , Genoma Humano , Hibridación de Ácido Nucleico , Adolescente , Niño , Preescolar , Bandeo Cromosómico , Femenino , Eliminación de Gen , Humanos , Lactante , Masculino , Mutación , Polimorfismo Genético , Síndrome

RESUMEN

About 15% of patients with a clinical phenotype of Angelman syndrome (AS) have an unknown etiology. We report a patient with features reminiscent of AS, including a pattern of characteristic facial anomalies as well as speech impairment, developmental delay and frequent laughter. In addition, the patient had features not commonly associated with AS such as heart malformations and scoliosis. She was negative in SNURF-SNRPN exon 1 methylation studies and the G-banded karyotype was normal. Array-based comparative genomic hybridization disclosed a deletion of maximally 1 Mb at 17q21.31. The deleted region contains the MAPT gene, implicated in late onset neurodegenerative disorders, and the STH and NP_056258.1 genes. Another gene, such as CRHR1, might also be included based on maximum possible size of the deletion. We suggest that microdeletions within the 17q21.31 segment should be considered as a possible cause of phenotypes resembling AS, particularly when easily controlled seizures and/or cardiac abnormalities are also present.

Asunto(s)

Cromosomas Humanos Par 17 , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Anomalías Múltiples/genética , Síndrome de Angelman/genética , Preescolar , Expresión Facial , Femenino , Humanos , Eliminación de Secuencia , Proteínas tau

RESUMEN

In total, 189 consecutive women diagnosed with SLE were evaluated using the ACR 1990 criteria for fibromyalgia. Patients were classified into three subgroups. The fibromyalgia group (FM) included patients experiencing pain on palpation in at least 11 of the 18 tender points examined, as well as having a history of widespread pain for at least three months. Patients who were noted to have pain in fewer than four quadrants with less than 11 of 18 tender points were considered to have regional pain (RP). All patients who did not meet criteria for either FM or RP were classified as having no pain (NP). Measurement of SLE disease activity, sleep complaints, depression, fatigue severity and health status were performed. Only 18 of the SLE patients (9.5%) (95% CI 5.3-14%) fulfilled the ACR criteria for the classification of FM. Of the patients, 106 (56.1%) fulfilled criteria for RP and had a number of tender points of 5.4 +/- 3.4, and the rest of the patients (34.4%) had no tenderness at specific tender point sites. Age, body mass index, educational level and disease duration were comparable between the groups. FM and RP groups had different patterns of symptoms prevalence, with dysmenorrhea being more distinctive for FM. Sleep disturbances were more severe in the FM than in the RP group. Daytime complaints such as sleepiness, fatigue and depression were similar for RP and FM groups, but patients with FM reported more disability. Fibromyalgia is not common in Mexican patients with SLE and has a different pattern of symptoms in RP and NP patients. These data add evidence that ethnicity can play an important role in FM manifestations.

Asunto(s)

Fibromialgia/etnología , Lupus Eritematoso Sistémico/etnología , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Evaluación de la Discapacidad , Femenino , Fibromialgia/clasificación , Fibromialgia/complicaciones , Humanos , Lupus Eritematoso Sistémico/complicaciones , México/epidemiología , Persona de Mediana Edad , Dimensión del Dolor , Prevalencia , Índice de Severidad de la Enfermedad , Trastornos del Sueño-Vigilia/etiología

RESUMEN

Blood Pb concentration in a South American toad Bufo arenarum population (n = 152) was determined over 10 samplings carried out between December 1996 and November 1999. The studied population lived in the surroundings of the La Plata City, the largest industrial-urban setting of the Buenos Aires Province, Argentina. The presence of the metal was detected in all the samples tested, the mean concentration range being 1.99-4.66 mg dl(-1). Some preliminary environmental data on soil content of Pb in the sampling area suggest the anthropogenic origin of the metal possibly due to high rate of Pb-containing gasoline utilisation until recently. The reported results may reflect a sequel of a sustained local air-soil-water pollution process.

Asunto(s)

Bufo arenarum/fisiología , Contaminantes Ambientales/sangre , Plomo/sangre , Animales , Argentina , Monitoreo del Ambiente , Contaminantes Ambientales/farmacocinética , Plomo/farmacocinética , Masculino , Población Urbana , Emisiones de Vehículos

RESUMEN

The effects of sublethal doses of lead (as acetate) on blood parameters of adult male Bufo arenarum were studied. Toads received one single injection with 10, 25, 50 or 100 mg/kg of body weight, equivalent to approximately 1/90-1/10 of the 120 h-LD50; seven days after the injections, the hematocrit and the blood delta-aminolevulinic acid dehydratase (ALAD) activity were measured. Hematocrit of lead-injected animals did not exhibit significant changes respective to controls that received sodium acetate (range 29.8-38.8%). Blood lead concentrations were positively and significantly correlated with the injected metal doses. Blood ALAD activity declined proportionately to the doses of the metal as well as to its whole blood concentration. Because of its sensitivity and specificity, it was concluded that the activity of delta-ALAD may be adopted as a reliable biomarker of Bufo arenarum experimental lead intoxication.

Asunto(s)

Bufo arenarum/sangre , Plomo/sangre , Porfobilinógeno Sintasa/sangre , Animales , Biomarcadores , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/toxicidad , Hematócrito , Masculino , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/toxicidad , Porfobilinógeno Sintasa/antagonistas & inhibidores , Sensibilidad y Especificidad , Contaminantes Químicos del Agua/toxicidad

RESUMEN

Two-thirds of patients affected by Duchenne or Becker muscular dystrophy (DMD/BMD) carry large intra-genic deletions in the dystrophin gene. In males, the deletions can be efficiently detected using multiplex polymerase chain reaction (PCR) and Southern blotting. In contrast, deletion detection in carrier females is complicated by the presence of a normal gene copy on the second X-chromosome. We have analyzed the boundaries of 570 deletions and 34 duplications in the dystrophin gene identified in the São Paulo and Leiden diagnostic laboratories. The data were used to select an optimal set of cosmid probes for the detection of the most frequently deleted areas of the dystrophin gene. Six cosmids were evaluated in fluorescence in situ hybridization (FISH) experiments to assess deletions in 21 heterozygous deletion-carriers and nine controls. No discrepancy was found between the FISH analysis and the molecular data, demonstrating the accuracy of the technique for carrier detection in Duchenne and Becker muscular dystrophy.

Asunto(s)

Distrofina/genética , Genes/genética , Distrofias Musculares/genética , Sondas de ADN , Exones/genética , Eliminación de Gen , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Distrofias Musculares/diagnóstico

RESUMEN

The effects on red blood cells of a single sublethal dose of Pb of 100 mg kg-1 administrated to adult Bufo arenarum were studied. The blood d-aminolevulinic acid dehydratase (d-ALAD) activity, the red blood cell (RBC) osmotic fragility (OF), and the hematocrit (Hct) were measured in control and lead poisoned toad. The enzyme d-ALAD is considered as a specific biomarker for human and animals lead exposure. In Bufo, lead also provoked a significant decrease in the d-ALAD activity without changes in the Hct. OF test was used to compare the impact of Pb on the extent of the RBC hemolysis produced by osmotic stress. Experimental data (absorbance of solubilized hemoglobin and [NaCl]) were fitted to the Orcutt et al. equation (1995) that allows a precise characterization of the parameters involved in OF. In blood from injected toads, the OF resulted significantly reduced. These changes were interpreted as a consequence of alterations in the composition and conformation of the RBC membrane due to Pb, as it was described for human erythrocytes.

Asunto(s)

Eritrocitos/fisiología , Intoxicación por Plomo/sangre , Fragilidad Osmótica , Animales , Bufo arenarum , Hematócrito , Porfobilinógeno Sintasa/sangre

RESUMEN

Cytogenetic studies of normal and tumor cells in a patient with gonadal dysgenesis and bilateral gonadoblastoma were performed. The karyotype was 46,XY in peripheral blood lymphocytes and skin fibroblasts. The conserved region of the SRY gene was detected by polymerase chain reaction amplification. Sequencing of this region did not reveal any alterations. A 46,XY chromosome constitution was observed in the right gonadoblastoma, but a partial deletion of chromosome 13 was present in the left tumor. This deletion included band 13q14, where the retinoblastoma gene is mapped. The study of the polymorphism of the variable number of tandem repeats region in intron 17 of the RB1 locus disclosed loss of heterozygosity in both the left tumor, which showed the deletion of chromosome 13, and in the right tumor, where no chromosome alterations of chromosome 13 were detected. In situ hybridization covering 130 kb of RB1 showed that a partial deletion of one of the RB1 alleles had occurred in the right tumor. Since the deletions affected different alleles in each tumor, independent events must have been involved in the development of the tumors. These findings point toward a significant role of RB1 in the development of gonadoblastoma.

Asunto(s)

Eliminación de Gen , Genes de Retinoblastoma , Disgenesia Gonadal 46 XY/genética , Gonadoblastoma/genética , Adolescente , Bandeo Cromosómico , Cromosomas Humanos Par 13 , Exones , Femenino , Disgenesia Gonadal 46 XY/complicaciones , Gonadoblastoma/complicaciones , Humanos , Hibridación Fluorescente in Situ , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN

RESUMEN

We report on a folate sensitive fragile site at Xq27-28 in a girl with a multiple congenital anomalies and mental retardation syndrome, who also carries a duplication of the long arm of chromosome 8. The fragile site was shown by FISH to be distal to both FRAXA and FRAXE. DNA hybridisation with probe OxF14 showed the amplification of the CGG repeats of locus FRAXF in the patient and in her clinically normal mother.

Asunto(s)

Cromosomas Humanos Par 8/genética , Síndrome del Cromosoma X Frágil/genética , Familia de Multigenes/genética , Southern Blotting , Niño , Bandeo Cromosómico , Citogenética , Femenino , Floxuridina/farmacología , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Linfocitos , Cromosoma X/genética

RESUMEN

We report on a 15-year-old girl with mental retardation, obesity, short stature and minor anomalies. She had 47 chromosomes with a minute extra ring which was identified by FISH to be derived from chromosome 17.

Asunto(s)

Cromosomas Humanos Par 17 , Discapacidad Intelectual/genética , Obesidad/genética , Adolescente , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Síndrome , Trisomía