Determinação das alterações genômicas em pacientes com malformações congênitas
Carregando...
Data
2018-11-09
Autores
Oliveira, Jakeline Santos
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
As ACs são alterações visíveis nos cromossomos, classificadas como numéricas e estruturais. Atualmente o grande desafio da genética clínica é classificar e associar a relevância clínica dos desequilíbrios genéticos ao fenótipo dos portadores. O trabalho tem como objetivo principal caracterizar desequilíbrio genômico sem diagnóstico sindrômico previamente descritos pelas técnicas de citogenética clássica, molecular visando apurar os pontos de quebras e genes inseridos na região cromossômica alterada por meio da citogenômica em estudos de casos. Foram feitas análises por citogenética (bandamento GTG), citogenética molecular (FISH) e citogenômica (array-CGH) em três pacientes com malformações congênitas não-sindrômicas para definição diagnóstica e maior conhecimento sobre a correlação genótipo-fenótipo. Foram redigidos estudos de casos de três pacientes portadores de MCs, atraso do desenvolvimento e deficiência intelectual. O primeiro copilado de caso trata-se de paciente do sexo feminino com anomalias esqueléticas, deficiência intelectual e atraso do desenvolvimento. O cariótipo da paciente é 46,XX[11]/47,XX,+mar[9]. A análise de array-CGH revelou dois ganhos/duplicações nas bandas cromossômicas 6p11.2q12 (10.335 Mb de tamanho) e 6q14.1q14.3 (10.765 Mb de tamanho). Por meio da técnica da FISH e os resultados do array-CGH a região duplicada 6q14.1q14.3 encontra-se inserida em um cromossomo marcador, oriundo do cromossomo 6. Os sinais clínicos descritos na paciente foram semelhantes a outros pacientes com duplicação da região 6q14. Os genes PGM3, MYO6 e IMPG1 foram associados a alterações sensoriais, imunodeficiência e cardiomiopatia hipertrófica. Poucos são os casos na literatura com pacientes descritos com duplicação envolvendo as regiões 6q11-6q16. O segundo copilado de caso trata-se de paciente do sexo feminino com dimorfismo fácil, atraso do desenvolvimento e deficiência intelectual. O cariótipo apresentou o resultado: 46,XX, dup(12)(p13.1-p11.2). Por meio da técnica de array-CGH foi detectado o ganho genético de aproximadamente 28 Mb na região cromossômica 12p13.31-p11.1. A alteração cromossômica observada na paciente é descrita como duplicação 12p parcial. Os genes GRIN2B, ATF7IP, ALG10, SYT10, DNM1L, PKP2, PIK3C2G, SCNN1A, PIANP e SOX5 foram sobrepostos a CNVs de ganho, classificadas como patogênicos correlacionadas aos fenótipos de face dismórfica, convulsões, disfunção cognitiva e distúrbios do neurodesenvolvimento. A alteração presente na paciente é similar aos sinais clínicos descritos em indivíduos na literatura. O terceiro copilado de caso trata-se de paciente do sexo feminino com hemiface, incisivo central único, deficiência intelectual, atraso do desenvolvimento e deficiência na fala. O cariótipo apresentou o resultado: 46,XX, t(1;14)(p36.2;q23). A translocação aparentemente equilibrada t(1;14) presente na paciente e do tipo de novo, com pouco casos recorrentes na literatura. Por meio da técnica de array-CGH foram caracterizadas duas perdas/deleções cromossômicas, nas regiões cromossômicas 14q13.1-q13.3 (2,1 Mb de tamanho) e Xp22.31 (1,7 Mb de tamanho). A deleção da região cromossômica 14q13 é descrita como menor região sobreposta (SRO) ao locus HPE8 para o espectro de holoprosencefalia (HPE). Os genes EAPP, SNX6, TULIP1 e NKX2, são descritos na literatura como potenciais genes candidatos a HPE e doenças neurológicas. A microdeleção da região cromossômica Xp22.1 apresenta os genes VCX3A e STS xii descritos na literatura alterados em doenças neurológicas. Os sinais clínicos presentes em nossa paciente em similaridade com os descritos na literatura e alteração nas bandas cromossômicas 14q13.1-q13.3 permitem associação com a microforma de HPE. No geral, a técnica de array-CGH que dispõem de resoluções a nível de kb, foi fundamental para a elucidação dos achados genômicos em todos os pacientes. Este estudo contribui com a correlação genótipo-fenótipo e consequentemente com a literatura científica a respeito das alterações cromossômicas não sindrômicas descritas nos copilados de caso.
The ACs are visible changes in the chromosomes, classified as numerical and structural. Currently the great challenge of clinical genetics is to classify and associate the clinical relevance of genetic imbalances with the phenotype of the carriers. The main objective of this work is to characterize genomic imbalance without syndromic diagnosis previously described by the classical and molecular cytogenetic techniques, in order to determine the breakpoints and genes inserted in the chromosomal region altered by cytogenetics in case studies. Cytogenetics (GTG banding), molecular cytogenetics (FISH) and cytogenetics (array-CGH) were performed in three patients with non-syndromic congenital malformations for diagnostic definition and greater knowledge on genotype-phenotype correlation. Case studies of three patients with MCs, developmental delay and intellectual disability were written. The first case file is a female patient with skeletal anomalies, intellectual disability and developmental delay. The patient's karyotype is 46, XX [11] / 47, XX, + sea [9]. The array-CGH analysis revealed two gains / doublings in the chromosomal bands 6p11.2q12 (10,335 Mb in size) and 6q14.1q14.3 (10,765 Mb in size). Through the FISH technique and the results of the array-CGH the duplicate region 6q14.1q14.3 is inserted in a chromosome marker, coming from chromosome 6. The clinical signs described in the patient were similar to other patients with duplication of the region 6q14. The genes PGM3, MYO6 and IMPG1 were associated with sensory alterations, immunodeficiency and hypertrophic cardiomyopathy. There are few cases in the literature with patients described with duplication involving the 6q11-6q16 regions. The second case file is a female patient with easy dimorphism, developmental delay and intellectual disability. The karyotype presented the result: 46, XX, dup (12) (p13.1-p11.2). Using the array-CGH technique, the genetic gain of approximately 28 Mb was detected in the chromosomal region 12p13.31-p11.1. The chromosomal abnormality observed in the patient is described as partial duplication. The genes GRIN2B, ATF7IP, ALG10, SYT10, DNM1L, PKP2, PIK3C2G, SCNN1A, PIANP and SOX5 were superimposed on gain CNVs, classified as pathogenic correlated to dysmorphic face phenotypes, convulsions, cognitive dysfunction and neurodevelopmental disorders. The present alteration in the patient is similar to the clinical signs described in individuals in the literature. The third case file is a female patient with hemiface, single central incisor, intellectual disability, developmental delay and speech deficiency. The karyotype presented the result: 46, XX, t (1; 14) (p36.2; q23). The apparently balanced translocation t (1; 14) present in the patient is of the new type, with few recurrent cases in the literature. By means of the array-CGH technique, two losses / chromosomal deletions were characterized, in the chromosomal regions 14q13.1-q13.3 (2.1 Mb in size) and Xp22.31 (1,7 Mb in size). The deletion of the 14q13 chromosomal region is described as a reduced overlap region (ORS) at the HPE8 locus for the holoprosencephaly (HPE) spectrum. EAPP, SNX6, TULIP1 and NKX2 genes are described in the literature as potential candidate genes for HPEs and neurological diseases. The microdeletion of chromosomal region Xp22.1 presents the genes VCX3A and STS described in the literature altered in neurological diseases. The clinical signs present in our patient in similarity to those described in the literature and alteration in the xiv 14q13.1-q13.3 chromosomal bands allow association with the microform of HPE. In general, the array-CGH technique that has resolutions at kb level was fundamental for the elucidation of genomic findings in all patients. This study contributes to the genotype-phenotype correlation and consequently to the scientific literature regarding the non-syndromic chromosomal changes described in the case files.
The ACs are visible changes in the chromosomes, classified as numerical and structural. Currently the great challenge of clinical genetics is to classify and associate the clinical relevance of genetic imbalances with the phenotype of the carriers. The main objective of this work is to characterize genomic imbalance without syndromic diagnosis previously described by the classical and molecular cytogenetic techniques, in order to determine the breakpoints and genes inserted in the chromosomal region altered by cytogenetics in case studies. Cytogenetics (GTG banding), molecular cytogenetics (FISH) and cytogenetics (array-CGH) were performed in three patients with non-syndromic congenital malformations for diagnostic definition and greater knowledge on genotype-phenotype correlation. Case studies of three patients with MCs, developmental delay and intellectual disability were written. The first case file is a female patient with skeletal anomalies, intellectual disability and developmental delay. The patient's karyotype is 46, XX [11] / 47, XX, + sea [9]. The array-CGH analysis revealed two gains / doublings in the chromosomal bands 6p11.2q12 (10,335 Mb in size) and 6q14.1q14.3 (10,765 Mb in size). Through the FISH technique and the results of the array-CGH the duplicate region 6q14.1q14.3 is inserted in a chromosome marker, coming from chromosome 6. The clinical signs described in the patient were similar to other patients with duplication of the region 6q14. The genes PGM3, MYO6 and IMPG1 were associated with sensory alterations, immunodeficiency and hypertrophic cardiomyopathy. There are few cases in the literature with patients described with duplication involving the 6q11-6q16 regions. The second case file is a female patient with easy dimorphism, developmental delay and intellectual disability. The karyotype presented the result: 46, XX, dup (12) (p13.1-p11.2). Using the array-CGH technique, the genetic gain of approximately 28 Mb was detected in the chromosomal region 12p13.31-p11.1. The chromosomal abnormality observed in the patient is described as partial duplication. The genes GRIN2B, ATF7IP, ALG10, SYT10, DNM1L, PKP2, PIK3C2G, SCNN1A, PIANP and SOX5 were superimposed on gain CNVs, classified as pathogenic correlated to dysmorphic face phenotypes, convulsions, cognitive dysfunction and neurodevelopmental disorders. The present alteration in the patient is similar to the clinical signs described in individuals in the literature. The third case file is a female patient with hemiface, single central incisor, intellectual disability, developmental delay and speech deficiency. The karyotype presented the result: 46, XX, t (1; 14) (p36.2; q23). The apparently balanced translocation t (1; 14) present in the patient is of the new type, with few recurrent cases in the literature. By means of the array-CGH technique, two losses / chromosomal deletions were characterized, in the chromosomal regions 14q13.1-q13.3 (2.1 Mb in size) and Xp22.31 (1,7 Mb in size). The deletion of the 14q13 chromosomal region is described as a reduced overlap region (ORS) at the HPE8 locus for the holoprosencephaly (HPE) spectrum. EAPP, SNX6, TULIP1 and NKX2 genes are described in the literature as potential candidate genes for HPEs and neurological diseases. The microdeletion of chromosomal region Xp22.1 presents the genes VCX3A and STS described in the literature altered in neurological diseases. The clinical signs present in our patient in similarity to those described in the literature and alteration in the xiv 14q13.1-q13.3 chromosomal bands allow association with the microform of HPE. In general, the array-CGH technique that has resolutions at kb level was fundamental for the elucidation of genomic findings in all patients. This study contributes to the genotype-phenotype correlation and consequently to the scientific literature regarding the non-syndromic chromosomal changes described in the case files.
Descrição
Palavras-chave
Alterações cromossômicas, Array-CGH, Anomalias congênitas, Deficiência intelectual, Atraso do desenvolvimento, Chromosomal alterations, Array-CGH, Congenital anomalies, Intellectual deficiency, Developmental delay