RESUMEN

The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

Asunto(s)

Síndrome de DiGeorge , Cardiopatías Congénitas , Humanos , Síndrome de DiGeorge/genética , Variaciones en el Número de Copia de ADN/genética , Brasil/epidemiología , Cardiopatías Congénitas/genética , Fenotipo

RESUMEN

BACKGROUND: The association of behavioural phenotype assessment with cytogenomic characterisation may provide a better comprehension of genotype-phenotype correlations in syndromes caused by chromosomal abnormalities, such as 18p deletion syndrome. METHOD: We report on four Brazilian patients with 18p deletion syndrome characterised by cytogenomic techniques and detailed neuropsychological evaluation. Intellectual, adaptive and behavioural characteristics were assessed through the Wechsler's Scales, the Vineland-II Scale and the Child Behaviour Checklist, respectively. Socio-economic measures including main caretaker educational level and family income as defined by Brazilian criteria for social class classification were also collected to evaluate a possible contribution of environmental factors in neurocognitive variability. RESULTS: Two out of four patients showed intellectual disability (IQ < 70). Wechsler's scale results suggest that in our sample, interpretation of social situations based on observation of non-verbal behaviour constitute a cognitive strength while judgement of social rules and language skills associated with word knowledge and verbal fluency may be a cognitive weakness. Concerning adaptive behaviour, motor and socialisation domains showed to better develop than communication and daily living skills on the Vineland-II Scale. Only one patient presented internalising behavioural problems based on the Child Behaviour Checklist. Our results also suggested that socio-economic status may contribute to overall patient development. CONCLUSION: Our results suggest that some 18p deletion syndrome patients may present average intellectual performance and that the segment deletion size and some families' socio-economic conditions may influence cognitive development.

Asunto(s)

Adaptación Psicológica , Deleción Cromosómica , Trastornos de los Cromosomas , Discapacidad Intelectual , Conducta Social , Factores Socioeconómicos , Adaptación Psicológica/fisiología , Adulto , Brasil , Niño , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/fisiopatología , Trastornos de los Cromosomas/psicología , Cromosomas Humanos Par 18/genética , Femenino , Pruebas Genéticas , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/psicología , Masculino , Adulto Joven

Asunto(s)

Anomalías Craneofaciales/genética , Proteínas de Unión al ADN/genética , Encefalocele/complicaciones , Cara/anomalías , Predisposición Genética a la Enfermedad/genética , Meningocele/complicaciones , Mutación , Factores de Transcripción/genética , Secuencia de Bases , Anomalías Craneofaciales/complicaciones , Homocigoto , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico

RESUMEN

Constitutional complex chromosomal rearrangements (CCRs) are considered rare cytogenetic events. Most apparently balanced CCRs are de novo and are usually found in patients with abnormal phenotypes. High-resolution techniques are unveiling genomic imbalances in a great percentage of these cases. In this paper, we report a patient with growth and developmental delay, dysmorphic features, nervous system anomalies (pachygyria, hypoplasia of the corpus callosum and cerebellum), a marked reduction in the ossification of the cranial vault, skull base sclerosis, and cardiopathy who presents a CCR with 9 breakpoints involving 4 chromosomes (3, 6, 8 and 14) and a 0.6-Mb deletion in 14q24.1. Although the only genomic imbalance revealed by the array technique was a deletion, the clinical phenotype of the patient most likely cannot be attributed exclusively to haploinsufficiency. Other events must also be considered, including the disruption of critical genes and position effects. A combination of several different investigative approaches (G-banding, FISH with different probes and SNP array techniques) was required to describe this CCR in full, suggesting that CCRs may be more frequent than initially thought. Additionally, we propose that a chain chromosome breakage mechanism may have occurred as a single rearrangement event resulting in this CCR. This study demonstrates the importance of applying different cytogenetic and molecular techniques to detect subtle rearrangements and to delineate the rearrangements at a more accurate level, providing a better understanding of the mechanisms involved in CCR formation and a better correlation with phenotype.

Asunto(s)

Cerebelo/anomalías , Aberraciones Cromosómicas , Rotura Cromosómica , Deleción Cromosómica , Malformaciones del Sistema Nervioso/genética , Bandeo Cromosómico , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 8/genética , Discapacidades del Desarrollo/genética , Reordenamiento Génico , Humanos , Lactante , Cariotipificación , Masculino , Cráneo , Translocación Genética

RESUMEN

Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes, generally equal in size or smaller than a chromosome 20 of the same metaphase spread. Most of them are unexpectedly detected in routine karyotype analyses, and it is usually not easy to correlate them with a specific clinical picture. A small group of sSMCs is derived from more than one chromosome, called complex sSMCs. Here, we report on a patient with a de novo complex sSMC, derived from chromosomes 8 and 14. Banding karyotype analysis, multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP)-based array, and fluorescence in situ hybridization (FISH) were performed to investigate its origin. Array and FISH analyses revealed a der(14)t(8;14)(p23.2;q22.1)dn. The propositus presents some clinical features commonly found in patients with partial duplication or triplication of 8p and 14q. This is the first report describing a patient with a congenital der(14)t(8;14)(p23.2;q22.1)dn sSMC.

Asunto(s)

Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 8/genética , Anomalías Múltiples/genética , Preescolar , Bandeo Cromosómico , Trastornos de los Cromosomas/patología , Factores de Transcripción Forkhead/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Reacción en Cadena de la Polimerasa Multiplex , Proteínas del Tejido Nervioso/genética , Fenotipo , Polimorfismo de Nucleótido Simple

RESUMEN

A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter→q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling.

Asunto(s)

Trastornos de los Cromosomas/genética , Adulto , Aneuploidia , Niño , Preescolar , Cromosomas Humanos Par 22/genética , Epigénesis Genética , Anomalías del Ojo , Femenino , Estudios de Seguimiento , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Adulto Joven

RESUMEN

We present a 2-year-old boy with a de novo 46,XY,idic(Y)(q11.221),del(4)(q26q31.1) karyotype. G-banding, FISH, MLPA, and SNP-array techniques were used to characterize the 24-Mb deletion in 4q and the breakpoint in the isodicentric Y-chromosome region between 15,982,252 and 15,989,842 bp. The patient presented with mild facial dysmorphism, hemangioma, mild frontal cerebral atrophy, and Dandy-Walker variant. Essentially, this case reveals that patients can present more complex genomic imbalances than initially suspected.

RESUMEN

The presence of a supernumerary 18p isochromosome is a rare chromosomal abnormality that results in 18p tetrasomy. This is a report on the clinical, cytogenetic and molecular findings of 2 non-related patients with a supernumerary 18p isochromosome. Both patients present some features of the 18p tetrasomy syndrome (strabismus, low-set ears, long and narrow fingers and toes), but additional characteristics were also observed. Cytogenetic analysis, FISH, MLPA and SNP array techniques showed that one of the isochromosomes is symmetric and monocentric, while the other is asymmetric and dicentric, yet resulting in a similar tetrasomy of the 18pter-18p10 region, followed by a partial 18q11.2 trisomy, an unprecedented finding in the literature.

Asunto(s)

Isocromosomas , Trisomía/genética , Niño , Cromosomas Humanos Par 18/genética , Análisis Citogenético , Epigénesis Genética , Femenino , Humanos , Lactante

RESUMEN

Ring chromosome 3 is a rare abnormality with only 10 patients described in the literature. We report a patient with r(3) and ∼6-Mb distal 3p deletion. Single nucleotide polymorphism array, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization techniques revealed that the ring was formed by a break in 3p26.1 and fusion with the subtelomeric region of 3q. The patient presents delayed psychomotor development, growth failure, minor anomalies and other features similar to patients with 3p monosomy. The analysis of 300 metaphase cells using G-banding and fluorescence in situ hybridization with centromeric probe revealed ring instability resulting in cells with secondary aberrations and with ring loss that could also be related to some phenotypic characteristics such as growth delay. This is the first patient with r(3) studied using molecular techniques that determined the exact breakpoints in order to establish a better karyotype-phenotype correlation.

Asunto(s)

Anomalías Múltiples/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 3/genética , Cromosomas en Anillo , Anomalías Múltiples/patología , Adolescente , Bandeo Cromosómico , Trastornos de los Cromosomas/patología , Trastornos del Crecimiento/patología , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Fenotipo , Trastornos Psicomotores/patología

RESUMEN

BACKGROUND: The most prevalent type of structural variation in the human genome is represented by copy number variations that can affect transcription levels, sequence, structure and function of genes. METHOD: In the present study, we used the multiplex ligation-dependent probe amplification (MLPA) technique and quantitative PCR for the detection of copy number variation in 132 intellectually disabled male patients with normal karyotypes and negative fragile-X-testing. RESULTS: Ten of these patients (7.6%) showed copy number variation in the subtelomeric regions, including deletions and duplications. DISCUSSION: Duplications of the SECTM1 gene, located at 17q25.3, and of the FLJ22115 gene, located at 20p13, could be associated with phenotype alterations. This study highlights the relevance in the aetiology of intellectual disability of subtelomeric rearrangements that can be screened by MLPA and other molecular techniques.

Asunto(s)

Dosificación de Gen/genética , Reordenamiento Génico/genética , Discapacidad Intelectual/genética , Telómero/genética , Adolescente , Niño , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Reacción en Cadena de la Polimerasa , Prevalencia

RESUMEN

Ring chromosomes are often associated with abnormal phenotypes due to loss of genomic material and also because of ring instability at mitosis after sister chromatid exchange events. We investigated ring chromosome instability in six patients with ring chromosomes 4, 14, 15, and 18 by examining 48- and 72-h lymphocyte cultures at the first, second and subsequent cell divisions after bromodeoxyuridine incorporation. Although most cells from all patients showed only one monocentric ring chromosome, ring chromosome loss and secondary aberrations were observed both in 48- and 72-h lymphocyte cultures and in metaphase cells of the different cell generations. We found no clear-cut correlation between ring size and ring instability; we also did not find differences between apparently complete rings and rings with genetic material loss. The cytogenetic findings revealed secondary aberrations in all ring chromosome patients. We concluded that cells with ring chromosome instability can multiply and survive in vivo, and that they can influence the patient's phenotype.

Asunto(s)

Inestabilidad Cromosómica/genética , Cromosomas en Anillo , Recuento de Células , Niño , Preescolar , Replicación del ADN , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Metafase , Embarazo

RESUMEN

Fragile X syndrome is one of the most frequent causes of mental retardation. Since the phenotype in this syndrome is quite variable, clinical diagnosis is not easy and molecular laboratory diagnosis is necessary. Usually DNA from blood cells is used in molecular tests to detect the fragile X mutation which is characterized by an unstable expansion of a CGG repeat in the fragile X mental retardation gene (FMR1). In the present study, blood and buccal cells of 53 mentally retarded patients were molecularly analyzed for FMR1 mutation by PCR. Our data revealed that DNA extraction from buccal cells is a useful noninvasive alternative in the screening of the FMR1 mutation among mentally retarded males.

Asunto(s)

ADN/análisis , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Pruebas Genéticas/métodos , Mucosa Bucal/química , Mutación/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Factibilidad , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/psicología , Humanos , Masculino , Reacción en Cadena de la Polimerasa

RESUMEN

Fragile X syndrome is one of the most frequent causes of mental retardation. Since the phenotype in this syndrome is quite variable, clinical diagnosis is not easy and molecular laboratory diagnosis is necessary. Usually DNA from blood cells is used in molecular tests to detect the fragile X mutation which is characterized by an unstable expansion of a CGG repeat in the fragile X mental retardation gene (FMR1). In the present study, blood and buccal cells of 53 mentally retarded patients were molecularly analyzed for FMR1 mutation by PCR. Our data revealed that DNA extraction from buccal cells is a useful noninvasive alternative in the screening of the FMR1 mutation among mentally retarded males.

Asunto(s)

Humanos , Masculino , Preescolar , Niño , Adolescente , Adulto , ADN , Pruebas Genéticas , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Mucosa Bucal/química , Mutación/genética , Estudios de Factibilidad , Síndrome del Cromosoma X Frágil/genética , Reacción en Cadena de la Polimerasa

RESUMEN

We present clinical and cytogenetic data on a family with a t(4;13)(p16;q11) translocation present in four generations. The balanced translocation resulted in one individual with monosomy 4p and one individual with trisomy 4p, due to 3:1 segregation. The male patient with trisomy 4p was fertile and transmitted the extra chromosome to his daughter.

Asunto(s)

Anomalías Múltiples/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 4/genética , Translocación Genética/genética , Trisomía/genética , Adulto , Preescolar , Bandeo Cromosómico , Segregación Cromosómica/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Linaje , Síndrome

RESUMEN

Lymphocyte cultures from five patients with chromosomal mosaicism (two 47,XY,+21/46,XY, one 47,XX,+21/46,XX, one 45,X/46,XX, and one 47,XXY/46,XY) were studied using sister chromatid differential staining technique for cell kinetic evaluation. Aneuploid and normal cell lines were compared to identify changes in cellular proliferation in vitro that could be related to cellular selective advantage and cell-line-proportion changes occurring with age. Comparison of the percentage of cells in different cell generations in 48, 72, and 96 h-cultures shows no differences between the aneuploid and normal cell lines indicating that cell-cycle kinetics is similar in these cells in vitro.

Asunto(s)

Ciclo Celular , Trastornos de los Cromosomas/genética , Mosaicismo/genética , Aneuploidia , Células Cultivadas , Preescolar , Cromátides/genética , Diploidia , Síndrome de Down/genética , Frecuencia de los Genes/genética , Humanos , Lactante , Cariotipificación , Cinética , Síndrome de Klinefelter/genética , Linfocitos/metabolismo , Metafase , Probabilidad , Síndrome de Turner/genética

RESUMEN

A three generation familial translocation (X;15)(p22;p11) is responsible for duplication (X)(pter-->p22) in two male and two female patients. It is present in a balanced state in the mothers and with the derivative chromosome 15 in the children. The Xp segment of the derivative chromosome 15 is separated from the X inactivation center and cannot undergo X inactivation. As a result, there is functional disomy of Xp in the male and female patients that is responsible for mental retardation and other phenotypic findings.

Asunto(s)

Anomalías Múltiples/genética , Duplicación de Gen , Aberraciones Cromosómicas Sexuales/genética , Translocación Genética , Cromosoma X , Adolescente , Adulto , Preescolar , Femenino , Humanos , Masculino , Linaje

RESUMEN

Fluorescent "in situ" hybridization (FISH) is the biggest recent advance in molecular cytogenetics, providing a valuable tool in analyzing genetic material. FISH permits a better evaluation of chromosomes and genes in metaphase cells as well as in interphase nuclei. This technique has a lot applications, especially in clinical and cancer cytogenetics.

Asunto(s)

Humanos , Citogenética/métodos , Cromosomas Humanos Par 10 , Hibridación Fluorescente in Situ

RESUMEN

Lymphocyte cultures from five patients with Werner's syndrome (WS) and five healthy controls revealed significantly slower proliferation kinetics in four out of five patients. Higher frequencies of chromosome aberration and aneuploidy were also present with evidence of variegated translocation mosaicism in one of the patients. The study revealed no differences in sister chromatid exchange frequencies.

Asunto(s)

Aberraciones Cromosómicas , Síndrome de Werner/genética , Adulto , Aneuploidia , División Celular , Células Cultivadas , Femenino , Humanos , Activación de Linfocitos , Linfocitos/inmunología , Masculino , Mosaicismo , Intercambio de Cromátides Hermanas

RESUMEN

We present 2 instances of Ullrich-Turner syndrome with mosaicism 45,X/46,X,idic(Xq)/47, X,idic(Xq),idic(Xq) and X-isochromosomes with 2 C-bands. The mosaicism with the 3 cell lines points to the presence of the isodicentric chromosome in the zygote and a subsequent nondisjunction event.

Asunto(s)

Anomalías Múltiples/genética , Amenorrea/genética , Aberraciones Cromosómicas/genética , Mosaicismo , Ovario/anomalías , Cromosoma X/ultraestructura , Adulto , Niño , Aberraciones Cromosómicas/patología , Bandeo Cromosómico , Trastornos de los Cromosomas , Compensación de Dosificación (Genética) , Femenino , Humanos , No Disyunción Genética

RESUMEN

The authors report on a patient with tetrasomy 9p and 9qh due a karyotype 47,XY,+dic(9)(q12) in lymphocytes and a normal karyotype in fibroblasts. Clinical and complementary investigation revealed a malformation syndrome with many anomalies like those of trisomy 9p as well as Dandy-Walker cyst and Hirschsprung disease not previously described in tetrasomy 9p.

Asunto(s)

Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 9 , Síndrome de Dandy-Walker/genética , Enfermedad de Hirschsprung/genética , Trastornos de los Cromosomas , Humanos , Recién Nacido , Cariotipificación , Masculino