ABSTRACT
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. .
Subject(s)
Female , Humans , Infant, Newborn , Male , Chromosome Aberrations , Comparative Genomic Hybridization/methods , Congenital Abnormalities/genetics , Neonatal Screening/methods , Congenital Abnormalities/diagnosis , Karyotyping , Oligonucleotide Array Sequence Analysis/methods , Retrospective StudiesABSTRACT
Neurofibromatosis type 1 (NF1) is one of the most commonly inherited autosomal dominant disorders. In order to determine whether genomic alterations and/or chromosomal aberrations involved in the malignant progression of NF1 were present in a Korean patient with NF1, molecular and cytogenetic analyses were performed on the pathologically normal, benign, and malignant tissues and primary cells cultured from those tissues of the patient. The comparative genomic hybridization (CGH) array revealed a Y chromosome loss in the malignant peripheral nerve sheet tumor (MPNST) tissue. G-banding analysis of 50 metaphase cells showed normal chromosomal patterns in the histopathologically normal and benign cultured cells, but a mosaic Y chromosome loss in the malignant cells. The final karyotype for the malignant cells from MPNST tissue was 45,X,-Y[28]/46,XY[22]. The data suggest that the somatic Y chromosome loss may be involved in the transformation of benign tumors to MPNSTs.
Subject(s)
Humans , Young Adult , Chromosomes, Human, Y/genetics , Nerve Sheath Neoplasms/genetics , Neurofibromatosis 1/geneticsABSTRACT
PURPOSE: Cri-du-Chat syndrome (CdCs) is a rare but clinically recongnizable condition with an estimated incidence of 1:50,000 live births. The clinical characteristics of the syndrome include severe psychomotor and mental retardation, microcephaly, hypertelorism, hypotonia, and slow growth. Also the size of the chromosome 5p deletion ranges were known from the region 5p13 to the terminal region. In this study, we report the spectrum of 5p deletion in Korean 20 pts. with CdCs and genotype-phenotype associations in CdCs. METHODS: In order to delineate genotype-phenotype correlation, molecular cytogenetic studies including GTG banding and clinical characterization were performed on Korean 20 pts with CdCs including parents. CGH array and Fluorescence in situ hybridization (FISH) analysis were used to confirm a terminal deletion karyotype and map more precisely the location of the deletion breakpoint. RESULTS: Molecular analysis of the spectrum of 5p deletion revealed 9 pts (45%) with a del (5)(p14), 7 pts. (35%) a del (5)(p13), 3 pts. (15%) a del (5)(p15.1) and 1 pt. (5%) a del (5)(p15.2) in 20 pts with CdCs. 4(20%)pts were identified to have additional chromosome abnormalites of deficiency and duplication involving chromosomes of 6, 8, 18, & 22. Parental study identified 3 familial case (2 paternal and 1 maternal origin) showing parents being a balanced translocation carrier. And the comparison study of the deletion break points among these 20 pts. with their phenotype has showed the varying clinical pheno-types in the CdCs critical region. CONCLUSION: The characterization of 5p deletion including parental study may help to delineate the genotypephenotype correlation in CdCs. Also these molecular cytogenetic analyses will be able to offer better information for accurate genetic diagnosis in CdCs and further make possible useful genetic counseling in pts. and family.