The radiological accident in Goiania in 1987 caused a trail of human contamination, animal, plant and environmental by a radionuclide. Exposure to ionizing radiation results in different types of DNA lesions. The mutagenic effects of ionizing radiation on the germline are special concern because they can endures for several generations, leading to an increase in the rate of mutations in children of irradiated parents. Thus, to evaluate the biological mechanisms of ionizing radiation in somatic and germline cells, with consequent determination of the rate mutations, is extremely important for the estimation of genetic risks. Recently it was established that Chromosomal Microarray Analysis is an important tool for detecting wide spectra of gains or losses in the human genome. Here we present the results of the effect of accidental exposure to low doses of ionizing radiation on the formation of CNVs in the progeny of a human population accidentally exposed to Caesium-137 during the radiological accident in Goiânia, Brazil.

BackgroundSupernumerary Marker Chromosomes consist in structurally abnormal chromosomes, considered as an extra chromosome in which around 70% occur as a de novo event and about 30% of the cases are mosaic. Tetrasomy 9p is a rare chromosomal abnormality described as the presence of a supernumerary isochromosome 9p. Clinical features of tetrasomy 9p include a variety of physical and developmental abnormalities.Case presentationHerein, we reported a postnatal case of a newborn who died in early infancy with multiple congenital malformations due to a mosaic de novo tetrasomy 9p detected by Chromosomal Microarray Analysis. Conventional cytogenetics analysis of the proband was 47,XY,+mar[45]/46,XY[5]. The parental karyotypes presented no visible numerical or structural alterations. Microarray Analysis of the proband revealed that the marker chromosome corresponded to a mosaic de novo gain at 9p24.3q21.11.ConclusionsChromosomal Microarray Analysis was helpful to identify the origin of the supernumerary marker chromosome and it was a powerful tool to carry out genetic diagnostic, guiding the medical diagnosis. Furthermore, the CMA allowed observing at the first time in Central Brazil the tetrasomy 9p and partial tetrasomy 9q in mosaic, encompassing a large duplicated region with several morbid genes, in an infant with multiple congenital malformations.

Intellectual disability is a complex, variable, and heterogeneous disorder, representing a disabling condition diagnosed worldwide, and the etiologies are multiple and highly heterogeneous. Microscopic chromosomal abnormalities and well-characterized genetic conditions are the most common causes of intellectual disability. Chromosomal Microarray Analysis analyses have made it possible to identify putatively pathogenic copy number variation that could explain the molecular etiology of intellectual disability. The aim of the current study was to identify possible submicroscopic genomic alterations using a high-density chromosomal microarray in a retrospective cohort of patients with otherwise undiagnosable intellectual disabilities referred by doctors from the public health system in Central Brazil. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had intellectual disability and a normal karyotype. The analysis detected 18 CNVs in 60% of patients. Pathogenic CNVs represented about 22%, so it was possible to propose the etiology of intellectual disability for these patients. Likely pathogenic and unknown clinical significance CNVs represented 28% and 50%, respectively. Inherited and de novo CNVs were equally distributed. We report the nature of CNVs in patients from Central Brazil, representing a population not yet screened by microarray technologies.

Koolen de Vries syndrome (KDVS; MIM 610443) is a genomic disorder caused by a recurrent microdeletion derived from nonallelic homologous recombination mediated by flanking segmental duplications. Clinical manifestations of this syndrome are characterized by intellectual disability, hypotonia, a friendly behavior, distinctive facial features, and epilepsy. Herein, we report a case of 2 girls who revealed global developmental delay, mild facial dysmorphisms, friendly behavior, and epileptic seizure with a de novo 17q21.31 microdeletion detected by chromosomal microarray analysis (CMA). Conventional cytogenetics analysis by GTG-banding showed a female karyotype 46,XX for both girls. CMA revealed a microdeletion spanning approximately 500 kb in 17q21.31 in both girls, encompassing the following genes: CRHR1, MGC57346, CRHR1-IT1, MAPT-AS1, SPPL2C, MAPT, MAPT-IT1, STH, and KANSL1. Haploinsufficiency of one or more of these genes within the deleted region is the most probable cause of the probands' phenotype and is responsible for the phenotype seen in KDVS. CMA is a powerful diagnostic tool and an effective method to identify the de novo 17q21.31 microdeletion associated with KDVS in our probands.

BackgroundChromosome abnormalities that segregate with a disease phenotype can facilitate the identification of disease loci and genes. The relationship between chromosome 18 anomalies with severe intellectual disability has attracted the attention of cytogeneticists worldwide. Duplications of the X chromosome can cause intellectual disability in females with variable phenotypic effects, due in part to variations in X-inactivation patterns. Additionally, deletions of the 7qter region are associated with a range of phenotypes.ResultsWe report the first case of de novo microdeletion at 7q and 18p, 18q partial trisomy, microduplication at Xp associated to intellectual disability in a Brazilian child, presenting a normal karyotype. Karyotyping showed any chromosome alteration. Chromosomal microarray analysis detected a de novo microdeletion at 18p11.32 and 18q partial trisomy, an inherited microdeletion at 7q31.1 and a de novo microduplication at Xp22.33p21.3.ConclusionsOur report illustrates a case that presents complex genomic imbalances which may contribute to a severe clinical phenotypes. The rare and complex phenotypes have to be investigated to define the subsets and allow the phenotypes classification.

The chromosome 22q11.2 region has long been implicated in genomic diseases. Some genomic regions exhibit numerous low copy repeats with high identity in which they provide increased genomic instability and mediate deletions and duplications in many disorders. DiGeorge Syndrome is the most common deletion syndrome and reciprocal duplications could be occurring in half of the frequency of microdeletions. We described five patients with phenotypic variability that carries deletions or reciprocal duplications at 22q11.2 detected by Chromosomal Microarray Analysis. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had clinical indication to global developmental delay and a normal karyotype. We observed in our study three microdeletions and two microduplications in 22q11.2 region with variable intervals containing known genes and unstudied transcripts as well as the LCRs that are often flanking and within this genomic rearrangement. The identification of these variants is of particular interest because it may provide insight into genes or genomic regions that are crucial for specific phenotypic manifestations and are useful to assist in the quest for understanding the mechanisms subjacent to genomic deletions and duplications.

ABSTRACT. We describe the first postnatal diagnosis of a child from Central Brazil with de novo cytogenetic alterations in 13q showing malformations of the brain, eyes, distal limbs, and genitourinary tract, and severe intellectual disability. The karyotype was a constitutive 46,XX,r (13)

Intellectual Disability (ID) is a neurodevelopmental disorder that affects approximately 3% of children and adolescents worldwide. It is a heterogeneous and multifactorial clinical condition. Several methodologies have been used to identify the genetic causes of ID and in recent years new generation sequencing techniques, such as exome sequencing, have enabled an increase in the detection of new pathogenic variants and new genes associated with ID. The aim of this study was to evaluate exome sequencing with analysis of the ID gene panel as a tool to increase the diagnostic yield of patients with ID/GDD/MCA in Central Brazil, together with karyotype and CMA tests. A retrospective cohort study was carried out with 369 patients encompassing both sexes. Karyotype analysis was performed for all patients. CMA was performed for patients who did not present structural and or numerical alterations in the karyotype. Cases that were not diagnosed after performing karyotyping and CMA were referred for exome sequencing using a gene panel for ID that included 1,252 genes. The karyotype identified chromosomal alterations in 34.7% (128/369). CMA was performed in 83 patients who had normal karyotype results resulting in a diagnostic yield of 21.7% (18/83). Exome sequencing with analysis of the ID gene panel was performed in 19 trios of families that had negative results with previous methodologies. With the ID gene panel analysis, we identified mutations in 63.1% (12/19) of the cases of which 75% (9/12) were pathogenic variants,8.3% (1/12) likely pathogenic and in 16.7% (2/12) it concerned a Variant of Uncertain Significance. With the three methodologies applied, it was possible to identify the genetic cause of ID in 42.3% (156/369) of the patients. In conclusion, our studies show the different methodologies that can be useful in diagnosing ID/GDD/MCA and that whole exome sequencing followed by gene panel analysis, when combined with clinical and laboratory screening, is an efficient diagnostic strategy.