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Endometriosis is a complex disease that affects 10-15% of women of reproductive age. Familial studies show that relatives of affected patients have a higher risk of developing the disease, implicating a genetic role for this disorder. Little is known about the impact of germline genomic copy number variant (CNV) polymorphisms on the heredity of the disease. In this study, we describe a rare CNV identified in two sisters with familial endometriosis, which contain genes that may increase the susceptibility and progression of this disease. We investigated the presence of CNVs from the endometrium and blood of the sisters with endometriosis and normal endometrium of five women as controls without the disease using array-CGH through the Agilent 2x400K platform. We excluded common CNVs that were present in the database of genomic variation. We identified, in both sisters, a rare CNV gain affecting 113kb at band 3q12.2 involving two candidate genes: ADGRG7 and TFG. The CNV gain was validated by qPCR. ADGRG7 is located at 3q12.2 and encodes a G protein-coupled receptor influencing the NF-kappaß pathway. TFG participates in chromosomal translocations associated with hematologic tumor and soft tissue sarcomas, and is also involved in the NF-kappa B pathway. The CNV gain in this family provides a new candidate genetic marker for future familial endometriosis studies. Additional longitudinal studies of affected families must confirm any associations between this rare CNV gain and genes involved in the NF-kappaß pathway in predisposition to endometriosis.

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Abstract Endometriosis is a complex disease that affects 10-15% of women of reproductive age. Familial studies show that relatives of affected patients have a higher risk of developing the disease, implicating a genetic role for this disorder. Little is known about the impact of germline genomic copy number variant (CNV) polymorphisms on the heredity of the disease. In this study, we describe a rare CNV identified in two sisters with familial endometriosis, which contain genes that may increase the susceptibility and progression of this disease. We investigated the presence of CNVs from the endometrium and blood of the sisters with endometriosis and normal endometrium of five women as controls without the disease using array-CGH through the Agilent 2x400K platform. We excluded common CNVs that were present in the database of genomic variation. We identified, in both sisters, a rare CNV gain affecting 113kb at band 3q12.2 involving two candidate genes: ADGRG7 and TFG. The CNV gain was validated by qPCR. ADGRG7 is located at 3q12.2 and encodes a G protein-coupled receptor influencing the NF-kappaβ pathway. TFG participates in chromosomal translocations associated with hematologic tumor and soft tissue sarcomas, and is also involved in the NF-kappa B pathway. The CNV gain in this family provides a new candidate genetic marker for future familial endometriosis studies. Additional longitudinal studies of affected families must confirm any associations between this rare CNV gain and genes involved in the NF-kappaβ pathway in predisposition to endometriosis.

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Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.

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Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.

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Hepatoblastoma (HB) is a rare embryonal tumor, although it is the most common pediatric liver cancer. The aim of this study was to provide an accurate cytogenomic profile of this type of cancer, for which information in cancer databases is lacking. We performed an extensive literature review of cytogenetic studies on HBs disclosing that the most frequent copy number alterations (CNAs) are gains of 1q, 2/2q, 8/8q, and 20; and losses at 1p and 4q. Furthermore, the CNA profile of a Brazilian cohort of 26 HBs was obtained by array-CGH; the most recurrent CNAs were the same as shown in the literature review. Importantly, HBs from female patients, high-risk stratification tumors, tumors who developed in older patients (> 3 years at diagnosis) or from patients with metastasis and/or deceased carried a higher diversity of chromosomal alterations, specifically chromosomal losses at 1p, 4, 11q and 18q. In addition, we distinguished three major CNA profiles: no detectable CNA, few CNAs and tumors with complex genomes. Tumors with simpler genomes exhibited a significant association with the epithelial fetal subtype of HBs; in contrast, the complex genome group included three cases with epithelial embryonal histology, as well as the only HB with HCC features. A significant association of complex HB genomes was observed with older patients who developed high-risk tumors, metastasis, and deceased. Moreover, two patients with HBs exhibiting complex genomes were born with congenital anomalies. Together, these findings suggest that a high load of CNAs, mainly chromosomal losses, particularly losses at 1p and 18, increases the tendency to HB aggressiveness. Additionally, we identified six hot-spot chromosome regions most frequently affected in the entire group: 1q31.3q42.3, 2q23.3q37.3, and 20p13p11.1 gains, besides a 5,3 Mb amplification at 2q24.2q24.3, and losses at 1p36.33p35.1, 4p14 and 4q21.22q25. An in-silico analysis using the genes mapped to these six regions revealed several enriched biological pathways such as ERK Signaling, MicroRNAs in Cancer, and the PI3K-Akt Signaling, in addition to the WNT Signaling pathway; further investigation is required to evaluate if disturbances of these pathways can contribute to HB tumorigenesis. The analyzed gene set was found to be associated with neoplasms, abnormalities of metabolism/homeostasis and liver morphology, as well as abnormal embryonic development and cytokine secretion. In conclusion, we have provided a comprehensive characterization of the spectrum of chromosomal alterations reported in HBs and identified specific genomic regions recurrently altered in a Brazilian HB group, pointing to new biological pathways, and relevant clinical associations.

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Cat eye syndrome (CES) is a rare chromosomal disorder that may be evident at birth. A small supernumerary chromosome is present, frequently has 2 centromeres, is bisatellited, and represents an inv dup(22)(q11) in those affected. It's known that the 22q11 region is associated with disorders involving higher and lower gene dosages. Conditions such as CES, 22q11 microduplication syndrome (Dup22q11) and oculoauriculovertebral spectrum phenotype (OAVS) may share genes belonging to this same region, which is known to have a predisposition to chromosomal rearrangements. The conditions, besides being related to chromosome 22, also share similar phenotypes. Here we have added a molecular evaluation update and results found of the first patient described with CES and OAVS phenotype, trying to explain the potential mechanism involved in the occurrence of this association.

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Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males. Consequently, the knowledge about X-linked ID (XLID) in females is still scarce. Herein, we used extreme XCI skewing (≥ 90%) to predict X-linked variants in females with idiopathic ID. XCI profiles from 53 probands were estimated from blood and buccal mucosa through a methylation-sensitive AR/RP2 assay. DNA samples with extreme XCI skewing were then submitted to array-comparative genomic hybridization and whole-exome sequencing. Seven females (13.2%) exhibited extreme XCI skewing, a percentage significantly higher than expected for healthy females in our population. XLID-potentially related variants were identified in five patients with extreme XCI skewing, including one pathogenic rstructural rearrangement [der(X) chromosome from a t(X;2)] and four single nucleotide variants in NLGN4X, HDAC8, TAF1, and USP9X genes, two of which affecting XCI escape genes. XCI skewing showed to be an outstanding approach for the characterization of molecular mechanisms underlying XLID in females. Beyond expanding the spectrum of variants/phenotypes associated with ID, our results pointed to compensatory biological pathways underlying XCI and uncover new insights into the involvement of escape genes on XLID, impacting genetic counseling.

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VACTERL association (OMIM 192350) is a heterogeneous clinical condition characterized by congenital structural defects that include at least 3 of the following features: vertebral abnormalities, anal atresia, heart defects, tracheoesophageal fistula, renal malformations, and limb defects. The nonrandom occurrence of these malformations and some familial cases suggest a possible association with genetic factors such as chromosomal alterations, gene mutations, and inherited syndromes such as Fanconi anemia (FA). In this study, the clinical phenotype and its relationship with the presence of chromosomal abnormalities and FA were evaluated in 18 patients with VACTERL association. For this, a G-banded karyotype, array-comparative genomic hybridization, and chromosomal fragility test for FA were performed. All patients (10 female and 8 male) showed a broad clinical spectrum: 13 (72.2%) had vertebral abnormalities, 8 (44.4%) had anal atresia, 14 (77.8%) had heart defects, 8 (44.4%) had esophageal atresia, 10 (55.6%) had renal abnormalities, and 10 (55.6%) had limb defects. Chromosomal abnormalities and FA were ruled out. In 2 cases, the finding of microalterations, namely del(15)(q11.2) and dup(17)(q12), explained the phenotype; in 8 cases, copy number variations were classified as variants of unknown significance and as not yet described in VACTERL. These variants comprise genes related to important cellular functions and embryonic development.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder, with strong genetic influences as evidenced by its high heritability. Submicroscopic variations (ranging from one kilobase to several megabases) in DNA, called copy number variations (CNVs), have been associated with psychiatric diseases, including ASD. We aimed to identify CNVs in children diagnosed with idiopathic ASD. We used microarray-based comparative genomic hybridization analysis to detect the CNVs, and bioinformatic tools to evaluate their pathogenic potential, based on predicted functional aspects. Using combined cytogenetic and bioinformatic tools, we identified an autism network of genes/proteins related to the CNVs. Among the 40 children analyzed, we found 14 potentially pathogenic CNVs, including those previously associated with ASD (located at 16p11.2, 15q11.2, and 7p21 regions). We suggest that the most relevant biological process and functional attributes involve olfactory receptors. The CNV-related autism network comprised 90 proteins and 754 nodes and indicated the family of olfactory receptors as a significant pathway in ASD. Olfactory receptors were previously associated with neurologic diseases, and they are possibly related to cognition. This integrative analysis that combines cytogenetics and bioinformatics is a promising approach to understand complex conditions such as ASD.

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BACKGROUND: Array-based comparative genome hybridization (array CGH) is a first-line test used in the genetic evaluation of individuals with multiple anomalies, developmental delays, and cognitive deficits. In this study, we analyzed clinical indications and findings of array CGH tests of Colombian individuals forwarded to a reference laboratory over a period of seven years in order to evaluate the diagnostic performance of the test in our population. RESULTS: The results of 1374 array CGH analyses of Colombian individuals were referred to the Andean Reference Institute in Colombia (Instituto de Referencia Andino) during a 7-year period (2009-2015). Chromosomal imbalances were detected in 488 cases (35%), whereas 121 cases were classified as nonpathogenic variants, 65 cases (4.7%) were classified as variants of uncertain significance, and 302 cases (22%) were classified as abnormal or pathogenic. The most common findings in the abnormal and/or pathogenic set were deletions, followed by duplications and complex rearrangements. Variants in the carrier status of autosomal recessive diseases were identified as incidental findings in 29 subjects (2%). CONCLUSIONS: Clinical indications preceding the referral of aCGH in Colombian patients are not standardized and result in unexpected pathogenic variants as well as secondary findings that need careful interpretation. Development of local infrastructure will probably improve the communication between all stakeholders, to ensure accurate clinical diagnoses.

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Myeloid neoplasms are a heterogeneous group of hematologic disorders with divergent patterns of cell differentiation and proliferation, as well as divergent clinical courses. Rare recurrent genetic abnormalities related to this group of cancers are associated with poor outcomes. One such abnormality is the MECOM gene rearrangement that typically occurs in cases with chromosome 7 abnormalities. MECOM encodes a transcription factor that plays an essential role in cell proliferation and maintenance and also in epigenetic regulation. Aberrant expression of this gene is associated with reduced survival. Hence, its detailed characterization provides biological and clinical information relevant to the management of pediatric myeloid neoplasms. In this work, we describe a rare karyotype harboring three copies of MECOM with overexpression of the gene in a child with a very aggressive myeloid neoplasm. Cytogenetic studies defined the karyotype as 46,XX,der(7)t(3;7)(q26.2;q21.2). Array comparative genomic hybridization (aCGH) revealed a gain of 26.04 Mb in the 3q26.2-3qter region and a loss of 66.6 Mb in the 7q21.2-7qter region. RT-qPCR analysis detected elevated expression of the MECOM and CDK6 genes (458.5-fold and 35.2-fold, respectively). Overall, we show the importance of performing detailed molecular cytogenetic analysis of MECOM to enable appropriate management of high-risk pediatric myeloid neoplasms.

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Duplications of the long arm of chromosome 1 are rare. Distal duplications are the most common and have been reported as either pure trisomy or unbalanced translocations. The paucity of cases with pure distal 1q duplications has made it difficult to delineate a partial distal trisomy 1q syndrome. Here, we report 2 patients with overlapping 1q duplications detected by G-banding. Array CGH and FISH were performed to characterize the duplicated segments, exclude the involvement of other chromosomes and determine the orientation of the duplication. Patient 1 presents with a mild phenotype and carries a 22.5-Mb 1q41q43 duplication. Patient 2 presents with a pure 1q42.13qter inverted duplication of 21.5 Mb, one of the smallest distal 1q duplications ever described and one of the few cases characterized by array CGH, thus contributing to a better characterization of distal 1q duplication syndrome.

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BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients. METHODS: Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools. RESULTS: Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients. CONCLUSIONS: These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.

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BACKGROUND: Wilms tumor (WT) has a not completely elucidated pathogenesis. DNA copy number alterations (CNAs) are common in cancer, and often define key pathogenic events. The aim of this work was to investigate CNAs in order to disclose new candidate genes for Wilms tumorigenesis. RESULTS: Array-CGH of 50 primary WTs without pre-chemotherapy revealed a few recurrent CNAs not previously reported, such as 7q and 20q gains, and 7p loss. Genomic amplifications were exclusively detected in 3 cases of WTs that later relapsed, which also exhibited an increased frequency of gains affecting a 16.2 Mb 1q21.1-q23.2 region, losses at 11p, 11q distal, and 16q, and WT1 deletions. Conversely, aneuploidies of chromosomes 13 and 19 were found only in WTs without further relapse. The 1q21.1-q23.2 gain associated with WT relapse harbours genes such as CHD1L, CRABP2, GJA8, MEX3A and MLLT11 that were found to be over-expressed in WTs. In addition, down-regulation of genes encompassed by focal deletions highlighted new potential tumor suppressors such as CNKSR1, MAN1C1, PAQR7 (1p36), TWIST1, SOSTDC1 (7p14.1-p12.2), BBOX and FIBIN (11p13), and PLCG2 (16q). CONCLUSION: This study confirmed the presence of CNAs previously related to WT and characterized new CNAs found only in few cases. The later were found in higher frequency in relapsed cases, suggesting that they could be associated with WT progression.

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Approximately a hundred patients with terminal 10q deletions have been described. They present with a wide range of clinical features always accompanied by delayed development, intellectual disability and craniofacial dysmorphisms. Here, we report a girl and a boy with craniosynostosis, developmental delay and other congenital anomalies. Karyotyping and molecular analysis including Multiplex Ligation dependent probe amplification (MLPA) and Array Comparative Genomic Hybridization (aCGH) were performed in both patients. We detected a 13.1 Mb pure deletion at 10q26.12-q26.3 in the girl and a 10.9 Mb pure deletion at 10q26.13-q26.3 in the boy, both encompassing about 100 genes. The clinical and molecular findings in these patients reinforce the importance of the DOCK1 smallest region of overlap I (SRO I), previously suggested to explain the clinical signs, and together with a review of the literature suggest a second 3.5 Mb region important for the phenotype (SRO II). Genotype-phenotype correlations and literature data suggest that the craniosynostosis is not directly related to dysregulated signaling in suture development, but may be secondary to alterations in brain development instead. Further, genes at 10q26 may be involved in the molecular crosstalk between brain and cranial vault.

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Terminal deletion in the short arm of chromosome 1 results in a disorder described as 1p36 deletion syndrome. The resulting phenotype varies among patients including mental retardation, developmental delay, sensorineural hearing loss, seizures, heart defects, and distinct facies. In the present case, we performed array-comparative genomic hybridization in a boy with multiple congenital malformations presenting some features overlapping the 1p36 deletion phenotype for whom chromosomal analysis did not reveal a terminal deletion in 1p. Results showed complex chromosome rearrangements involving the 1p36.33-p35.3 region. While the mechanism of origin of these rearrangements is still unclear, chromothripsis-a single catastrophic event leading to shattering chromosomes or chromosome regions and rejoining of the segments-has been described to occur in a fraction of cancers. The presence of at least 12 clustered breaks at 1p and apparent lack of mosaicism in the present case suggests that a single event like chromothripsis occurred. This finding suggests that chromothripsis is responsible for some constitutive complex chromosome rearrangements.

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OBJECTIVE: To identify novel genetic causes of syndromic hearing loss in Brazil. DESIGN: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. STUDY SAMPLE: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. RESULTS: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. CONCLUSIONS: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

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The chromosome interval 10p15.3p14 harbors about a dozen genes. This region has been implicated in a few well-known human phenotypes, namely HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) and DGS2 (DiGeorge syndrome 2), but a number of variable phenotypes have also been reported. Cleft lip/palate seems to be a very unusual finding within the clinical spectrum of patients with this deletion. Here, we report a male child born with short stature, cleft lip/palate, and feeding problems who was found to have a 5.6-Mb deletion at 10p15.3p14.

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OBJECTIVE: To identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array-CGH) in DNA samples of neonates with congenital anomalies of unknown cause from a birth defects monitoring program at a public maternity hospital. METHODS: A blind genomic analysis was performed retrospectively in 35 stored DNA samples of neonates born between July of 2011 and December of 2012. All potential DNA copy number variations detected (CNVs) were matched with those reported in public genomic databases, and their clinical significance was evaluated. RESULTS: Out of a total of 35 samples tested, 13 genomic imbalances were detected in 12/35 cases (34.3%). In 4/35 cases (11.4%), chromosomal imbalances could be defined as pathogenic; in 5/35 (14.3%) cases, DNA CNVs of uncertain clinical significance were identified; and in 4/35 cases (11.4%), normal variants were detected. Among the four cases with results considered causally related to the clinical findings, two of the four (50%) showed causative alterations already associated with well-defined microdeletion syndromes. In two of the four samples (50%), the chromosomal imbalances found, although predicted as pathogenic, had not been previously associated with recognized clinical entities. CONCLUSIONS: Array-CGH analysis allowed for a higher rate of detection of chromosomal anomalies, and this determination is especially valuable in neonates with congenital anomalies of unknown etiology, or in cases in which karyotype results cannot be obtained. Moreover, although the interpretation of the results must be refined, this method is a robust and precise tool that can be used in the first-line investigation of congenital anomalies, and should be considered for prospective/retrospective analyses of DNA samples by birth defect monitoring programs. .

OBJETIVO: Identificar desequilíbrios cromossômicos por meio da hibridização genômica comparativa baseada em microarranjos (CGH-array) em amostras de DNA de neonatos com anomalias congênitas de causa desconhecida de um programa de monitoramento de defeitos congênitos em uma maternidade pública. MÉTODOS: Uma análise genômica cega foi realizada retrospectivamente em 35 amostras armazenadas de DNA de neonatos nascidos entre julho de 2011 e dezembro de 2012. Todas as possíveis variações no número de cópias (CNVs) de DNA foram comparadas com as relatadas em bases de dados genômicos públicas, e sua relevância clínica foi avaliada. RESULTADOS: De um total de 35 amostras testadas, foram detectados 13 desequilíbrios genômicos em 12/35 casos (34,3%). Em 4/35 casos (11,4%), os desequilíbrios cromossômicos poderiam ser definidos como patogênicos; em 5/35 (14,3%) deles foram identificadas CNVs de DNA de relevância clínica incerta; e, em 4/35 (11,4%), foram detectadas variações normais. Dentre os quatro casos com resultados considerados relacionados causalmente aos achados clínicos, 2/4 (50%) apresentaram alterações causais já relacionadas a síndromes de microdeleção bem definidas. Em 2/4 amostras (50%), os desequilíbrios cromossômicos encontrados, embora preditivos como patogênicos, não estavam relacionados anteriormente a entidades clínicas reconhecidas. CONCLUSÕES: A análise de CGH-array permitiu maior taxa de detecção de anomalias cromossômicas, e essa determinação é valiosa principalmente em neonatos com anomalias congênitas de etiologia desconhecida ou em casos em que os resultados do cariótipo não podem ser obtidos. Além disso, embora a interpretação dos resultados deva ser refinada, esse método é uma ferramenta robusta e precisa que pode ser usada na investigação de primeira linha de anomalias congênitas e deve ser considerada em análises futuras/retrospectivas de amostras de DNA por programas de monitoramento de defeitos congênitos. .

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OBJECTIVE: To identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array-CGH) in DNA samples of neonates with congenital anomalies of unknown cause from a birth defects monitoring program at a public maternity hospital. METHODS: A blind genomic analysis was performed retrospectively in 35 stored DNA samples of neonates born between July of 2011 and December of 2012. All potential DNA copy number variations detected (CNVs) were matched with those reported in public genomic databases, and their clinical significance was evaluated. RESULTS: Out of a total of 35 samples tested, 13 genomic imbalances were detected in 12/35 cases (34.3%). In 4/35 cases (11.4%), chromosomal imbalances could be defined as pathogenic; in 5/35 (14.3%) cases, DNA CNVs of uncertain clinical significance were identified; and in 4/35 cases (11.4%), normal variants were detected. Among the four cases with results considered causally related to the clinical findings, two of the four (50%) showed causative alterations already associated with well-defined microdeletion syndromes. In two of the four samples (50%), the chromosomal imbalances found, although predicted as pathogenic, had not been previously associated with recognized clinical entities. CONCLUSIONS: Array-CGH analysis allowed for a higher rate of detection of chromosomal anomalies, and this determination is especially valuable in neonates with congenital anomalies of unknown etiology, or in cases in which karyotype results cannot be obtained. Moreover, although the interpretation of the results must be refined, this method is a robust and precise tool that can be used in the first-line investigation of congenital anomalies, and should be considered for prospective/retrospective analyses of DNA samples by birth defect monitoring programs.

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