Comparison of results of prenatal diagnosis by different techniques for fetuses with increased nuchal translucency / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) and trio-whole exome sequencing (trio-WES) for fetuses with increased nuchal translucency (NT) thickness.@*METHODS@#Sixty two pregnant women who had visited Urumqi Maternal and Child Care Health Hospital between June 2018 and June 2020 for NT ≥ 3.0 mm at 11 ~ 13+6 gestational weeks were selected as study subjects. Relevant clinical data were collected. The patients were divided into 3.0 ~ ＜3.5 mm (n = 33) and ≥3.5 mm groups (n = 29). Chromosome karyotyping analysis and chromosomal microarray analysis were carried out. And trio-WES analysis was performed on 15 samples with NT thickening but negative CMA results. The distribution and incidence of chromosomal abnormalities in the two groups were compared by using chi-square test.@*RESULTS@#The median age of the pregnant women was 29 years old (22 ~ 41 years old), the median thickness of NT was 3.4 mm (3.0 ~ 9.1 mm), and the median gestational age at the detection was 13+4 weeks (11+5 ~ 13+6 weeks). Chromosome karyotyping analysis has detected 12 cases of aneuploidies and 1 case of derivative chromosome. The detection rate was 20.97% (13/62). CMA has detected 12 cases of aneuploidies, 1 case of pathogenic CNV and 5 cases of variant of uncertain significance (VUS), with a detection rate of 29.03% (18/62). The aneuploidy rate for the NT ≥ 3.5 mm group was higher than that for the 3.0 ≤ NT < 3.5 mm group [3.03% (1/33) vs. 41.38% (12/29), χ² = 13.698, P < 0.001]. There was no statistically significant difference between the two groups in the detection rate of fetal pathogenic CNV and VUS (χ² = 0.028, P > 0.05). Trio-WES analysis of 15 samples with negative CMA result and no structural abnormality has identified 6 heterozygous variants, including SOS1: c.3542C>T (p.A1181V) and c.3817C>G (p.L1273V), COL2A1: c.436C>T (p.P146S) and c.3700G>A (p.D1234N), LZTR1: c.1496T>C (p.V499A), and BRAF: c.64G>A (p.D22N), respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were rated as VUS.@*CONCLUSION@#NT thickening can indicate chromosome abnormality, and CMA and trio-WES may be used for the prenatal diagnosis.

Síndrome de Down y su pesquisa durante el primer trimestre de la gestación / Down Syndrome and Screening During Pregnancy First Trimester

RESUMEN Introducción: La pesquisa prenatal de anomalías cromosómicas, mediante el uso de marcadores epidemiológicos y ecográficos del primer trimestre permite identificar gestantes con riesgo incrementado de síndrome de Down. Objetivos: Analizar la edad materna, la translucencia nucal, el ductus venoso y el hueso nasal, durante el cribaje del primer trimestre, en las gestantes que se realizaron diagnóstico prenatal citogenético, con el fin de evaluar la efectividad del mismo en la detección temprana del síndrome Down y su utilidad para la reducción del número de pruebas invasivas. Métodos: Se realizó un estudio descriptivo retrospectivo de corte transversal y se analiza una muestra de 3439 gestantes a las que se realizó el estudio citogenético indicado en el Centro Provincial de Genética Médica de La Habana, en el período comprendido entre el 3 de enero de 2006 y el 30 de diciembre de 2008. Resultados: La edad materna avanzada mostró una sensibilidad de un 87 por ciento del test y una tasa de falsos positivos de 99 por ciento. La translucencia nucal se comportó con una sensibilidad de 10 por ciento. El hueso nasal no mostró asociación con los cariotipos positivos para síndrome de Down. Al no realizarse sistemáticamente la presencia del ductus venoso, no se pudo establecer una asociación estadística. La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas. Conclusiones: La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas(AU)

ABSTRACT Introduction: The prenatal investigation of chromosomal abnormalities through the use of epidemiological and echographic markers on the first trimester, allows to identify pregnant women with an increased risk of Down syndrome. Objectives: To analyze maternal age, nuchal translucency, venous ductus and nasal bone, during the first trimester screening, in pregnant women who underwent prenatal cytogenetic diagnosis, in order to evaluate effectiveness in early detection of Down syndrome and the value for reducing the number of invasive tests. Methods: A descriptive retrospective cross-sectional study was carried out and a sample of 3439 pregnant women was studied. The cytogenetic study ordered at Havana Provincial Center for Medical Genetics was carried out from January 3, 2006 to December 30, 2008. Results: Advanced maternal age showed 87 percent sensitivity and 99 percent of false positive rate. Nuchal translucency accounted 10 percent of sensitivity. The nasal bone showed no association with positive karyotypes for Down syndrome. A statistical association of the venous ductus presence could not be established since the search was not systematically. Conclusions: The estimation of Down syndrome risk based solely on advanced maternal age determines high false positive rate. Therefore, this marker, together with the evaluation of the first trimester ultrasound markers for recalculating the individual risk, can increase the diagnostic effectiveness and decrease the number of invasive tests(AU)

Image Settings Affecting Nuchal Translucency Measurement Using Volume NT(TM) Software

PURPOSE: To evaluate the effects of the deviation from the mid-sagittal plane, fetal image size, tissue harmonic imaging (THI), and speckle reduction filter (SRF) on the measurement of the nuchal translucency (NT) thickness using Volume NT(TM) software. MATERIALS AND METHODS: In 79 pregnant women, NT was measured using Volume NT(TM). Firstly, the three-dimensional volumes were categorized based on the angle of deviation in 10degrees intervals from the mid-sagittal plane. Secondly, the operator downsized the fetal image to less than 50% of the screen (Method A) and by magnifying the image (Method B). Next, the image was magnified until the fetal head and thorax occupied 75% of the screen, and the NT was measured (Method C). Lastly, NT values were acquired with THI and SRF functions on, with each function alternately on, and with both functions off. RESULTS: The mean differences in NT measurements were -0.09 mm (p<0.01) between two-dimensional (2D) and a deviation of 31-40degrees and -0.10 mm (p<0.01) between 2D and 41-50degrees. The intraclass correlation coefficients (ICC) for 2D-NT and NT according to image size were 0.858, 0.923, and 0.928 for methods A, B, and C, respectively. The ICC for 2D-NT and NT with respect to the THI and SRF were 0.786, 0.761, 0.740, and 0.731 with both functions on, THI only, SRF only, and with both functions off, respectively. CONCLUSION: NT measurements made using Volume NT(TM) are affected by angle deviation from the mid-sagittal plane and fetal image size. Additionally, the highest correlation with 2D-NT was achieved when THI and SRF functions were used.

Valor de los marcadores epidemiológicos y sonográficos del primer trimestre como indicadores de riesgo de cromosomopatías / Value of first trimester epidemiologic and sonographic markers as chromosome-diseases risk indicators

La pesquisa prenatal de anomalías cromosómicas mediante el uso de marcadores epidemiológicos y sonográficos del primer trimestre, permite identificar gestantes con riesgo incrementado de cromosomopatías, se ofrece la opción del diagnóstico prenatal citogenético. OBJETIVOS: realizar una evaluación preliminar de la utilidad de los marcadores ecográficos del primer trimestre, como predictores de anomalías cromosómicas en las gestantes que se realizaron diagnóstico prenatal citogenético. MÉTODOS: se realizó un estudio descriptivo retrospectivo de corte transversal con el objetivo de realizar una evaluación preliminar de la utilidad de los marcadores ultrasonográficos, como predictores de anomalías cromosómicas durante el primer trimestre. Para la realización de esta investigación fue analizada una muestra de 2 507 gestantes que se realizaron el estudio citogenético indicado en la consulta citogenética del Departamento Provincial de Genética de Ciudad de la Habana, perteneciente al Hospital Ginecoobstétrico Ramón González Coro, en el período comprendido entre enero del año 2006 y diciembre de 2007. RESULTADOS: la translucencia nucal elevada incrementó de forma significativa el riesgo de anomalías cromosómicas. El hueso nasal, no mostró asociación con los cariotipos positivos. Dada la no realización sistemática del ductus venoso, no se pudo establecer una asociación estadística. CONCLUSIONES la translucencia nucal aumentada, incrementó significativamente el riesgo de defectos cromosómicos, no obstante, su sensibilidad estuvo por debajo de lo previamente descrito en otras investigaciones

Prenatal screening of chromosomal anomalies using epidemiological and sonographic markers during the first trimester, allow identifying pregnant with high risk of chromosome disease; we offer the cytogenetics prenatal diagnosis as option. OBJECTIVES: to made a preliminary assessment on usefulness of echographic marker during the first trimester like predictors of chromosomal anomalies in pregnant with a cytogenetics prenatal diagnosis. METHODS: a descriptive, retrospective and cross-sectional study was conducted for a preliminary assessment on usefulness of ultrasonograpic markers like predictors of chromosomal anomalies during the first trimester. In research a sample including 2 507 pregnants with cytogenetics study prescribed in cytogenetics consultation of Genetics Provincial department of Havana City from the Ramón González Cor Gynecology-Obstetrics Hospital during January, 2006 and December, 2007. RESULTS: the high transillumination nuchal increased in a significant way the risk of chromosomal anomalies. Nasal bone has not association with other positive karyotypes. Given the no systemic performing of ductus venous, it was impossible to establish a statistical association. CONCLUSIONS: the increase nuchal transillumination increases significantly the risk of chromosomal defects; however, its sensitivity was below the previously described in other researches

Anomalias e prognóstico fetal associados à translucência nucal aumentada e cariótipo anormal / Fetal abnormalities and prognosis associated with increased nuchal translucency and abnormal karyotype

OBJETIVO: Descrever a frequência de anomalias cromossômicas em fetos com translucência nucal (TN) aumentada, e a frequência de malformações estruturais, a evolução e o resultado da gestação nos fetos com TN aumentada e cariótipo anormal. MÉTODOS: Estudo retrospectivo envolvendo 246 casos com medida da TN acima do percentil 95º para a idade gestacional, com cariótipo fetal conhecido ou avaliação clínica das crianças no período pós-natal. Os casos foram acompanhados no setor de Medicina Fetal do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. RESULTADOS: O resultado do cariótipo fetal esteve alterado em 14,2 por cento dos casos. O acompanhamento dessas gestações revelou anormalidade estruturais em 80,8 por cento dos fetos, sendo as anormalidades cardíacas as mais comuns (61,5 por cento). Resultados gestacionais adversos, como abortamento, óbitos intraútero e neonatal ocorreram em 76,5 por cento dos fetos. CONCLUSÃO: Translucência nucal aumentada, entre 11 - 13 semanas e 6 dias, é importante marcador de anomalias cromossômicas fetais e malformações estruturais fetais, principalmente cardíacas. Diante deste achado, há aumento do risco de abortamento, óbito intrauterino e neonatal para estas gestações.

OBJECTIVES: This study aimed to evaluate the incidence of chromosomal abnormalities in fetuses with increased nuchal translucency (NT) measurement. Incidence of structural abnormalities and pregnancy outcome was also described in fetuses with increased NT and abnormal karyotype. METHODS: This was a retrospective study involving 246 fetuses with increased NT and known karyotype followed at the Fetal Medicine Unit, Hospital das Clínicas, São Paulo University Medical School. RESULTS: Fetal karyotype was abnormal in 14.2 percent of the cases. Ultrasound anomaly scan and specialized echocardiographic studies in these cases showed fetal structural abnormalities in 80.8 percent and cardiac defects were found in 61.5 percent of the fetuses. Pregnancy outcome was abnormal in 76.5 percent of these women. CONCLUSION: Increased NT measurement at 11 to 13 weeks and 6 days is an important marker for fetal chromosomal and structural abnormalities, mainly fetal cardiac defects. This finding also indicates increased risk of spontaneous fetal and neonatal death.

Threshold of Nuchal Translucency for the Detection of Chromosomal Aberration: Comparison of Different Cut-offs

This study evaluated the sensitivities and false positive rates of the screening test using ultrasonographic measurement of thickness of nuchal translucency (NT) with different cut-offs for chromosomal aberration in a Korean population. We included 2,570 singleton pregnancies undergoing ultrasound between 11 weeks and 14 weeks of gestation in this study. We analyzed the sensitivities of NT alone for screening chromosomal aberration using three cut-offs -2.5 mm, 3.0 mm, and 95th percentile for each crown rump length (CRL). There were 31 chromosomal aberrations (1.2%) including 12 cases of trisomy 21. The numbers of chromosomal aberrations that were detected by NT with different cut-offs of 2.5 mm, 3.0 mm and the 95th percentile CRL were 22, 18 and 23, respectively. At a threshold of 2.5 mm, the sensitivity and the false positive rate for total chromosomal aberrations were 67.7% and 6.3%, respectively. At 3.0 mm, those were 54.8% and 3.5%, respectively. At the 95th percentile CRL, those were 70.9% and 5.8%, respectively. The use of CRL-dependent cut-offs for nuchal translucency improves the detection of chromosomal aberrations when compared to fixed cut-offs in a Korean population.

Curva de referência para a medida da translucência nucal na população capixaba / Reference range curve of nuchal translucency in the population of the State of Espírito Santo, Brazil

OBJETIVO: Estudar o comportamento da medida da translucência nucal (TN) na população capixaba, no período entre a 10ª e a 14ª semanas de gestação. MATERIAIS E MÉTODOS: Estudou-se de forma transversal 853 fetos, consecutivamente, que apresentaram cariótipos ou fenótipos normais. Todos os fetos foram submetidos, durante a ultra-sonografia de rotina, à medida da TN. A análise estatística utilizou o teste "t" de Student e ANOVA. O teste de regressão ajustou o melhor modelo matemático para traduzir o comportamento da TN. RESULTADOS: A idade materna variou de 14 a 49 anos (média de 30,2 anos), sendo que 22,1 por cento encontravam-se com mais de 35 anos. A TN mostrou comportamento crescente com a idade gestacional e o comprimento cabeça-nádegas (CCN). Houve 73 casos (6,46 por cento) de fetos normais com TN maior que 2,5 mm. O melhor modelo matemático encontrado para representar o comportamento da TN foi a regressão linear simples (TN = 0,414 + 0,020 Î CCN), que permitiu estabelecer curva de normalidade com os percentis 5, 10, 25, 50, 75, 90 e 95. CONCLUSÃO: A TN apresenta comportamento crescente com o avançar da idade gestacional, no período de 10 a 14 semanas. A população capixaba apresenta medidas de TN semelhantes às demais populações já testadas.