Cytogenetic study of women with premature ovarian failure

Etiology of premature ovarian failure (POF) is unclear in most patients. Since some cases are related to X-chromosome abnormalities, cytogenetical studies were conducted in patients with POF. Lymphocyte cultures from eleven patients were compared to cultures from age-matched controls. All individuals presented normal karyotypes. Frequencies of aneuploid and structural chromosome aberrations did not differ between the groups. The X chromosome was more frequently involved in aneuploidy and in premature centromere division in both groups.A etiologia da insuficiência ovariana prematura (POF) ainda é desconhecida na maioria dos pacientes. Uma vez que alguns casos estão associados a anormalidades do cromossomo X, estudamos citogeneticamente pacientes portadores de POF. Comparamos as culturas de linfócitos de onze pacientes com as de indivíduos controles de mesmas idades. Todos os indivíduos estudados apresentaram cariótipos normais. As freqüências de células aneuplóides e com aberrações cromossômicas estruturais não diferiram entre os grupos. Verificamos uma maior freqüência de aneuploidia e de divisão prematura do centrômero do cromossomo X nos dois grupos.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Deleción 22q11.2 en pacientes con defecto cardiaco conotruncal y fenotipo del síndrome de la deleción 22q11.2

BACKGROUND: The 22q11.2 deletion syndrome is the most frequent human microdeletion syndrome. The phenotype is highly variable, being characterized by conotruncal heart defect, facial dysmorphisms, velopharyngeal insufficiency, learning difficulties and mental retardation. OBJECTIVE: The objective of this study was to investigate the frequency of deletion 22q11.2 in a Brazilian sample of individuals with isolated conotruncal heart defect and 22q11.2 deletion syndrome phenotype. METHODS: Twenty-nine patients were studied by classical cytogenetics, by fluorescence in situ hybridization (FISH), and by molecular techniques. RESULTS: Cytogenetic analysis by G-banding revealed a normal karyotype in all patients except one who presented a 47,XX,+idic(22)(q11.2) karyotype. Using molecular techniques, a deletion was observed in 25% of the patients, all exhibiting a 22q11.2 deletion syndrome phenotype. In none of the cases the deletion was inherited from the parents. The frequency of 22q11.2 deletion was higher in patients with the clinical spectrum of the 22q11.2 deletion syndrome than in patients with isolated conotruncal heart defect. CONCLUSION: Investigating the presence of the deletion and its correlation with the patients' clinical data can help the patients and their families to have a better genetic counseling and more adequate clinical follow-up.FUNDAMENTO: El síndrome de la deleción 22q11.2 es el más frecuente síndrome de microdeleción humana. El fenotipo, altamente variable, se caracteriza por defecto cardiaco conotruncal, dismorfias faciales, insuficiencia velofaríngea, dificultad de aprendizaje y retardo mental. OBJETIVO: El objetivo de este trabajo fue investigar la frecuencia tanto de la deleción 22q11.2 en una muestra brasileña de individuos portadores de cardiopatía conotrucal aislada, como del fenotipo del síndrome de la delación 22q11.2. MÉTODOS: Se estudiaron a 29 pacientes por medio de citogenética clásica, por hibridación in situ fluorescente (FISH) y también por técnicas moleculares. RESULTADOS: El análisis citogenético por medio de bandeo G reveló cariotipo normal en todos los pacientes, con excepción de uno, que presentó cariotipo 47,XX,+idic(22)(q11.2). Con la utilización de técnicas moleculares, se observó la deleción en el 25% de los pacientes, todos portadores del fenotipo del síndrome de la deleción 22q11.2. En ningún de los casos, la deleción se heredó de los padres. La frecuencia de la deleción 22q11.2 en el grupo de pacientes portadores del espectro clínico de este síndrome resultó mayor que en el grupo de pacientes con cardiopatía conotruncal aislada. CONCLUSIÓN: La investigación de la presencia de deleción y su correlación con los datos clínicos de los pacientes pueden auxiliar los pacientes y sus familias a tener un mejor aconsejamiento genético, así como un seguimiento clínico más adecuado.FUNDAMENTO: A síndrome da deleção 22q11.2 é a mais freqüente síndrome de microdeleção humana. O fenótipo é altamente variável e caracterizado por defeito cardíaco conotruncal, dismorfias faciais, insuficiência velofaríngea, dificuldade de aprendizagem e retardo mental. OBJETIVO: O objetivo deste trabalho foi investigar a freqüência da deleção 22q11.2 em uma amostra brasileira de indivíduos portadores de cardiopatia conontrucal isolada e do fenótipo da síndrome da deleção 22q11.2. MÉTODOS: Vinte e nove pacientes foram estudados por meio de citogenética clássica, por hibridação in situ fluorescente (FISH) e por técnicas moleculares. RESULTADOS: A análise citogenética por meio de bandamento G revelou cariótipo normal em todos os pacientes, com exceção de um que apresentou cariótipo 47,XX,+idic(22)(q11.2). Com o uso de técnicas moleculares, a deleção foi observada em 25% dos pacientes, todos portadores do fenótipo da síndrome da deleção 22q11.2. Em nenhum dos casos, a deleção foi herdada dos pais. A freqüência da deleção 22q11.2 foi maior no grupo de pacientes portadores do espectro clínico da síndrome da deleção 22q11.2 do que no grupo de pacientes com cardiopatia conotruncal isolada. CONCLUSÃO: A investigação da presença da deleção e sua correlação com os dados clínicos dos pacientes podem auxiliar os pacientes e suas famílias a terem um melhor aconselhamento genético e um seguimento clínico mais adequado.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Terminal 18q deletions are stabilized by neotelomeres

Background: All human chromosomes are capped by tandem repeat (TTAGGG)n sequences that protect them against end-to-end fusion and are essential to chromosomal replication and integrity. Therefore, after a chromosomal breakage, the deleted chromosomes must be stabilized by retaining the telomere or acquiring a new cap, by telomere healing or telomere capture. There are few reports with molecular approaches on the mechanisms involved in stabilization of 18q terminal deletions.Results: in this study we analyzed nine patients with 18q terminal deletion identified by G-banding and genomic array. FISH using PNA probe revealed telomeric signals in all deleted chromosomes tested. We fine-mapped breakpoints with customized arrays and sequenced six terminal deletion junctions. in all six deleted chromosomes sequenced, telomeric sequences were found directly attached to the breakpoints. Little or no microhomology was found at the breakpoints and none of the breaks sequenced were located in low copy repeat (LCR) regions, though repetitive elements were found around the breakpoints in five patients. One patient presented a more complex rearrangement with two deleted segments and an addition of 17 base pairs (bp).Conclusions: We found that all six deleted chromosomes sequenced were probably stabilized by the healing mechanism leading to a neotelomere formation.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilEmory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USAUniversidade Federal de São Paulo, Dept Biophys, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, Lab Citogenom, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, Lab Citogenom, BR-05403000 São Paulo, BrazilFAPESP: 2012/51150-0FAPESP: 2012/15572-7Web of Scienc

Clinical checklists in the selection of mentally retarded males for molecular screening of fragile X syndrome

Fragile X syndrome is the most frequent cause of inherited mental retardation. The phenotype in this syndrome is quite variable and less conspicuous in younger patients, making clinical diagnosis difficult and thus making molecular diagnosis necessary. The use of clinical checklists in mentally retarded individuals can help selecting patients to be given priority in the molecular investigation for the fragile-X mutation in the FMR1 gene. We evaluated two clinical checklists in a sample of 200 Brazilian male patients with mental retardation. The highest scores in the two checklists concentrated among the 19 males (9.5%) found to carry full mutations. Our results confirm the importance of fragile-X checklists as a clinical tool in the study of mentally retarded patients.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP)Universidade de São Paulo Instituto de Biociências Departamento de Genética e Biologia EvolutivaUNIFESPSciEL

Duplication 9p and their implication to phenotype

Background: Trisomy 9p is one of the most common partial trisomies found in newborns. We report the clinical features and cytogenomic findings in five patients with different chromosome rearrangements resulting in complete 9p duplication, three of them involving 9p centromere alterations.Methods: the rearrangements in the patients were characterized by G-banding, SNP-array and fluorescent in situ hybridization (FISH) with different probes.Results: Two patients presented de novo dicentric chromosomes: der(9; 15)t(9; 15)(p11.2;p13) and der(9; 21)t(9; 21) (p13.1;p13.1). One patient presented two concomitant rearranged chromosomes: a der(12)t(9; 12)(q21.13;p13.33) and an psu i(9)(p10) which showed FISH centromeric signal smaller than in the normal chromosome 9. Besides the duplication 9p24.3p13.1, array revealed a 7.3 Mb deletion in 9q13q21.13 in this patient. the break in the psu i(9) (p10) probably occurred in the centromere resulting in a smaller centromere and with part of the 9q translocated to the distal 12p with the deletion 9q occurring during this rearrangement. Two patients, brother and sister, present 9p duplication concomitant to 18p deletion due to an inherited der(18)t(9; 18)(p11.2; p11.31) mat.Conclusions: the patients with trisomy 9p present a well-recognizable phenotype due to facial appearance, although the genotype-phenotype correlation can be difficult due to concomitant partial monosomy of other chromosomes. the chromosome 9 is rich in segmental duplication, especially in pericentromeric region, with high degree of sequence identity to sequences in 15p, 18p and 21p, chromosomes involved in our rearrangements. Thus, we suggest that chromosome 9 is prone to illegitimate recombination, either intrachromosomal or interchromosomal, which predisposes it to rearrangements, frequently involving pericentromeric regions.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilUniv São Paulo, Dept Pathol, Lab Citogen, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilFAPESP: 2012/51150-0FAPESP: 2012/15572-7Web of Scienc

Allan-Herndon-Dudley syndrome in a female patient and related mechanisms.

peer reviewedAllan-Herndon-Dudley syndrome (AHDS) is characterized by neuropsychomotor developmental delay/intellectual disability, neurological impairment with a movement disorder, and an abnormal thyroid hormone profile. This disease is an X-linked disorder that mainly affects men. We described a female patient with a de novo variant in the SLC16A2 gene, a milder AHDS phenotype, and a skewed X chromosome inactivation profile. We discuss the mechanisms associated with the expression of the phenotypic characteristics in female patients, including SLC16A2 gene variants and cytogenomic alterations, as well as preferential inactivation of the normal X chromosome

Balanced X autosome translocation suggests association of AMMECR1 disruption with hearing loss short stature bone and heart alterations

Univ Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo, BrazilUniv Geneva, Dept Genet Med & Dev, Geneva, SwitzerlandUniv Lausanne, Ctr Integrat Genom, Lausanne, SwitzerlandBaylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USAHop Jeanne De Flandre, Clin Genet, Lille, FranceUniv Fed Sao Paulo, Dept Psychobiol, Sao Paulo, BrazilUniv Sao Paulo, Dept Pathol, Sao Paulo, BrazilFriedrich Schiller Univ, Inst Human Genet, Jena, GermanyHop Jeanne De Flandre, Inst Genet Med, Lille, FranceUniv Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Psychobiol, Sao Paulo, BrazilWeb of Scienc

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis