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BACKGROUND: The clinical heterogeneity of the 22q11.2 Deletion Syndrome (22q11.2DS - OMIM, #188400 and #192430) is a universal challenge leading to diagnostic delay. The aim of this study was to evaluate a low cost strategy for the diagnosis of this condition based upon clinical criteria previously reported. Health professionals, who collected clinical data, from twelve centers were trained in those criteria, which were summed through an online application (CranFlow). RESULTS: Clinical and laboratorial data of 347 individuals registered from 2008 to 2017 in the Brazilian Database on Craniofacial Anomalies/22q11.2 Deletion Syndrome, were reviewed. They were divided in two groups: (I) 168 individuals investigated before the definition of the criteria and (II) 179 individuals investigated after the criteria application. All of them were investigated for 22q11.2DS by Fluorescent in situ Hybridization (FISH) and/or Multiplex Ligation Probe-dependent Amplification (MLPA), detecting 98 cases with 22q11.2DS. Among the individuals with 22q11.2DS in Group II, 42/53 (79.25%) fulfilled the proposed criteria against 11/53 (20.75%) who did not fulfill them (p < .0001). The association of congenital heart diseases with high predictive value for 22q11.2DS and hypernasal voice were significantly associated to the presence of 22q11.2DS (p = 0.0172 and p < .0001, respectively). In addition, 22q11.2DS was confirmed 3.82 more times when the individuals fulfilled the proposed criteria. Of the 249 cases negative for the typical deletion in 22q11.2, Chromosomal Microarray Analysis (CMA) was performed in 132 individuals and detected pathogenic alterations at other genomic regions in 19 individuals, and variants of uncertain clinical significance in 31 cases. CONCLUSIONS: Therefore, a locus-specific approach could be used to individuals with positive criteria as a cost-effective alternative for 22q11.2DS diagnosis. The authors discuss advantages and suggest ways of implementing this approach to investigate 22q11.2DS in a public health system.

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Partial duplication of chromosome 3q - dup(3q) - is a recognizable syndrome with dysmorphic facial features, microcephaly, digital anomalies, and genitourinary and cardiac defects, as well as growth retardation and developmental delay. Most cases of dup(3q) result from unbalanced translocations or inversions and are accompanied by additional chromosomal imbalances. Pure dup(3q) is rare, and only 31 cases have been reported so far. We report a new case of a girl with a pure 2-Mb duplication at 3q26.2 not encompassing the known critical region 3q26.3q27. After an extensive review, to the best of our knowledge, the case herein presented harbors the shortest 3q duplication of this region. The clinical phenotype of this patient resembles previously reported cases of pure dup(3q) syndrome, including intellectual disability, synophrys, a wide nasal bridge, dysmorphic ears, clinodactyly, and cardiac defects. We suggest that the 3q26.2 duplication is a candidate copy number alteration explaining our patient's clinical phenotype.

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In the last few decades, different methods for the detection of genomic imbalances, such as the microdeletion syndromes, were developed. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and presents wide clinical heterogeneity. The aim of this study was to describe 4 unusual cases of genomic imbalances found in individuals with suspected microdeletion syndromes. Different methods were necessary to complete the diagnosis and to obtain information for genetic counseling. The study was retrospective and descriptive. From August 2014 to December 2015, 39 individuals were assessed using FISH and/or MLPA; in 15 cases, chromosomal microarray (CMA) analysis was carried out. Of 39 registered individuals, we found deletions in the 22q11.2 region in 10 individuals (8 individuals with 22q11.2DS and 2 individuals presenting with atypical deletions in the 22q11.2 region: 1 distal deletion and 1 central deletion). In one case with a typical 22q11.2 deletion, a familial balanced translocation was detected. In another case without a 22q11.2 deletion, a 6p duplication concomitant with a 9p deletion was detected by CMA. Clinical data are reported and diagnostic investigations are discussed. Essential aspects for the understanding of different diagnostic techniques of genomic imbalances are considered, and the 4 cases described underline the complexity and the difficulties involved in the diagnostic process. The approach is informative for clinical practice and may be applied in other contexts of genomic imbalance investigation in microdeletion syndromes.

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Deletions in the 10q22.3q23.2 region are rare and mediated by 2 low-copy repeats (LCRs 3 and 4). These deletions have already been recognized as the 10q22q23 deletion syndrome. The phenotype associated with this condition is rather uncharacteristic, and most common features are craniofacial dysmorphisms and developmental delay. We describe a boy with craniofacial dysmorphic features, developmental delay, tetralogy of Fallot, hand/foot abnormalities, and recurrent respiratory tract infections. Chromosomal microarray analysis disclosed a 7.8-Mb microdeletion at 10q22.3q23.2, flanked by LCRs 3/4, and an additional 16q12.1 microdeletion of 189 kb. This article reviews the clinical signs of reported cases with similar deletions and compares them with our patient, contributing to a better understanding of genotype-phenotype correlation.

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OBJECTIVE: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS). METHODS: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA). RESULTS: Clinically significant copy number variations (CNVs ≥300kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993kb duplication in 15q21.1 and 706kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD. CONCLUSION: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD.

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