Leslie Domenici Kulikowski

Pure duplication 1q41-qter: further delineation of trisomy 1q syndromes.

Several authors have attempted to characterize the partial 1q trisomy syndrome, reporting clinical features such as mental retardation, macrocephaly, large fontanels, prominent forehead, broad flat nasal bridge, high‐arched palate, micro/retrognathia, low‐set ears, and cardiac defects. However, defining the partial trisomy 1q syndrome is difficult, because it is a rare chromosomal abnormality and in most instances the trisomy 1q is combined with partial monosomy of another autosomal segment. We report on the clinical and molecular cytogenetic study of a patient who presents pure partial 1q duplication. This is the first case of pure duplication 1q41‐qter in the literature.

Breakpoint mapping in a case of mosaicism with partial monosomy 9p23 → pter and partial trisomy 1q41 → qter suggests neo-telomere formation in stabilizing the deleted chromosome

We report on a clinical and molecular cytogenetic study of a patient who presents a complex chromosomal rearrangement with two different cell lines. Using high‐resolution GTG banding and fluorescence in situ hybridization (FISH) with several probes, including bacterial artificial chromosomes (BACs), the karyotype was defined as 46,XX,del(9)(p23)[54]/46,XX,der(9)t(1;9)(q41;p23)[46], indicating the presence of monosomy 9p23 in all cells and trisomy 1q41 in approximately 50% of the cells. The patient studied presents most of the manifestations of the 9p deletion and 1q duplication syndromes. The breakpoint was mapped at 9p23 with a loss of approximately 13.9‐Mb of DNA. The duplicated segment consists of approximately 35 Mb from 1q41‐qter region. We also suggest that a mechanism for telomere capture and interstitial telomeric sequences (ITs) is involved in a neo‐telomere formation in one of the cell lines. This study highlights the importance of combining high‐resolution chromosome and FISH with BACs in order to make genotype–phenotype correlations and to understand the mechanisms involved chromosomal aberrations.

Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum.

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same approximately 3 or approximately 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.

Evaluation of clinical checklists for fragile X syndrome screening in Brazilian intellectually disabled males: proposal for a new screening tool.

Patients with fragile X syndrome present a variable phenotype, which contributes to the underdiagnosing of this condition. The use of clinical checklists in individuals with intellectual disability can help in selecting patients to be given priority in the molecular investigation of the fragile X mutation in the FMR1 gene. Some features included in checklists are better predictors than others, but they can vary among different populations and with patient age. In the present study, we evaluated 20 features listed in four clinical checklists from the literature, using a sample of 192 Brazilian male patients presenting with intellectual disability (30 positive and 162 negative for fragile X mutation). After statistical analysis, 12 out of the 20 items analyzed showed significant differences in their distributions between the two groups. These features were grouped in a new checklist that can help clinicians in their referral for fragile X testing in patients with developmental delay.

22q11.2 deletion in patients with conotruncal heart defect and del22q syndrome phenotype

FUNDAMENTO: El sindrome de la delecion 22q11.2 es el mas frecuente sindrome de microdelecion humana. El fenotipo, altamente variable, se caracteriza por defecto cardiaco conotruncal, dismorfias faciales, insuficiencia velofaringea, dificultad de aprendizaje y retardo mental. OBJETIVO: El objetivo de este trabajo fue investigar la frecuencia tanto de la delecion 22q11.2 en una muestra brasilena de individuos portadores de cardiopatia conotrucal aislada, como del fenotipo del sindrome de la delacion 22q11.2. METODOS: Se estudiaron a 29 pacientes por medio de citogenetica clasica, por hibridacion in situ fluorescente (FISH) y tambien por tecnicas moleculares. RESULTADOS: El analisis citogenetico por medio de bandeo G revelo cariotipo normal en todos los pacientes, con excepcion de uno, que presento cariotipo 47,XX,+idic(22)(q11.2). Con la utilizacion de tecnicas moleculares, se observo la delecion en el 25% de los pacientes, todos portadores del fenotipo del sindrome de la delecion 22q11.2. En ningun de los casos, la delecion se heredo de los padres. La frecuencia de la delecion 22q11.2 en el grupo de pacientes portadores del espectro clinico de este sindrome resulto mayor que en el grupo de pacientes con cardiopatia conotruncal aislada. CONCLUSION: La investigacion de la presencia de delecion y su correlacion con los datos clinicos de los pacientes pueden auxiliar los pacientes y sus familias a tener un mejor aconsejamiento genetico, asi como un seguimiento clinico mas adecuado.

Single-nucleotide polymorphism array-based characterization of ring chromosome 18.

OBJECTIVE To study genotype-phenotype correlation of ring chromosome 18 [r(18)] in 9 patients with 46,XN karyotype. STUDY DESIGN In 9 patients with a de novo 46,XN,r(18) karyotype (7 females, 2 males), we performed high-resolution single-nucleotide polymorphism array analysis (Illumina Human Omni1-QuadV1 array in 6 patients, Affymetrix 6.0 array in 3 patients), investigation of parental origin, and genotype-phenotype correlation. RESULTS No breakpoint was recurrent. Single metaphases with loss of the ring, double rings, or secondarily rearranged rings were found in some cases, but true mosaicism was present in none of these cases. In 3 patients, additional duplications in 18p (of 1.4 Mb, 2 Mb, and 5.8 Mb) were detected. In 1 patient, an additional deletion of 472 kb in Xp22.33, including the SHOX gene, was found. Parental origin of r(18) was maternal in 2 patients and paternal in 4 patients, and formation was most likely meiotic. Karyotype was normal in all investigated parents (n = 15). At birth, mean maternal age was 30 years (n = 9) and mean paternal age was 34.4 years (n = 9). CONCLUSION Genotype-phenotype correlation revealed extensive clinical variability but no characteristic r(18) phenotype. Severity of clinical signs were generally correlated with the size of the deletion. Patients with large deletions in 18p and small deletions in 18q exhibited mainly symptoms related to 18p-, whereas those with large deletions in 18q and small deletions in 18p had symptoms of 18q-.

Williams-Beuren Syndrome: A Clinical Study of 55 Brazilian Patients and the Diagnostic Use of MLPA

Williams-Beuren syndrome (WBS) is a genetic disease caused by a microdeletion in the 7q11.23 region. It is characterized by congenital heart disease, mainly supravalvular aortic stenosis, mental retardation, mild short stature, facial dysmorphisms, and variable abnormalities in different systems. Objectives. To report the clinical findings of 55 Brazilian patients confirmed by multiplex ligation-dependent probe amplification (MLPA). Methods. Patients were followed up for 4 years at the Genetics Unit of the Instituto da Criança of the Hospital das Clínicas, FMUSP, Brazil. A kit specific for WBS was used to detect the 7q11.23 microdeletion. Results. Two patients with negative FISH results had positive MLPA results for WBS. The characteristics of the patients with the deletion were as follows: typical WBS facies (98.2%), neuropsychomotor delay (98.2%), hypersocial behavior (94.5%), hyperacusis (94.5%), and congenital heart disease (81.8%). Conclusions. MLPA was effective in detecting the microdeletion in the 7q11.23 region to confirm the diagnosis of WBS. MLPA was also able to confirm the diagnosis of WBS in two patients with typical clinical characteristics but negative FISH results. Thus, MLPA is a promising method in the diagnostic investigation of WBS. WBS is a multisystemic disorder and therefore requires multidisciplinary care and specific follow-up to prevent complications.

45,X karyotype in an infertile man: how is this possible?

The case was male, 32 years old, with a nonobstructive azoospermia diagnosis and an initial 45,X karyotype. We evaluated by classical cytogenetic methods, C and NOR banding, fluorescent in situ hybridization, and polymerase chain reaction investigations. After investigation, we found the following karyotype: 45,X,dic(Y;22)(q11.223;p11.2). This investigation contributes to our understanding of how chromosome rearrangements can influence fertility processes and how important it is to perform a cytogenetic analysis in infertility cases.

Wide clinical variability in cat eye syndrome patients: four non-related patients and three patients from the same family.

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.

Deleção 22q11.2 em pacientes com defeito cardíaco conotruncal e fenótipo da síndrome da deleção 22q11.2

FUNDAMENTO: El sindrome de la delecion 22q11.2 es el mas frecuente sindrome de microdelecion humana. El fenotipo, altamente variable, se caracteriza por defecto cardiaco conotruncal, dismorfias faciales, insuficiencia velofaringea, dificultad de aprendizaje y retardo mental. OBJETIVO: El objetivo de este trabajo fue investigar la frecuencia tanto de la delecion 22q11.2 en una muestra brasilena de individuos portadores de cardiopatia conotrucal aislada, como del fenotipo del sindrome de la delacion 22q11.2. METODOS: Se estudiaron a 29 pacientes por medio de citogenetica clasica, por hibridacion in situ fluorescente (FISH) y tambien por tecnicas moleculares. RESULTADOS: El analisis citogenetico por medio de bandeo G revelo cariotipo normal en todos los pacientes, con excepcion de uno, que presento cariotipo 47,XX,+idic(22)(q11.2). Con la utilizacion de tecnicas moleculares, se observo la delecion en el 25% de los pacientes, todos portadores del fenotipo del sindrome de la delecion 22q11.2. En ningun de los casos, la delecion se heredo de los padres. La frecuencia de la delecion 22q11.2 en el grupo de pacientes portadores del espectro clinico de este sindrome resulto mayor que en el grupo de pacientes con cardiopatia conotruncal aislada. CONCLUSION: La investigacion de la presencia de delecion y su correlacion con los datos clinicos de los pacientes pueden auxiliar los pacientes y sus familias a tener un mejor aconsejamiento genetico, asi como un seguimiento clinico mas adecuado.