Genetic analysis and prenatal diagnosis of intellectual disability caused by Xq25 microduplication in a pedigree / 中华围产医学杂志

Objective:To analyze the clinical and genetic characteristics of a 27-year-old male patient with intellectual disability and his pedigree to provide a reference for genetic counseling and prenatal diagnosis.Methods:G-banding and array comparative genomic hybridization (aCGH) were performed to analyze the karyotypes and genomic copy number variations of the proband (Ⅲ-1) and his family members. Based on the results, prenatal diagnosis was performed for one pregnant woman (Ⅲ-2) in the pedigree who is the sister of the proband.Results:All karyotyping were normal in the family members, while aCGH results showed a 1 533 kb microduplication in the Xq25 region of the proband, his mother (Ⅱ-3), his uncle (Ⅱ-2), and his sister (Ⅲ-2), which was confirmed to be pathogenic. The proband and his uncle presented with intellectual disability, bradylalia, and facial dysmorphism. In contrast, his mother and sister showed normal phenotypes. His sister's fetal karyotype and aCGH results were normal, and the pregnancy continued. A male baby (Ⅳ-1) was delivered vaginally at term and showed no physical or intellectual abnormalities during a 46-month follow-up.Conclusions:Xq25 microduplication might be the cause of intellectual disability in the proband. STAG2 is probably the essential gene in Xq25 region.

Prenatal diagnosis indications and pregnancy outcomes and its impact factors in 1 372 pregnant women with fetal sex chromosome aneuploidy / 中华围产医学杂志

Objective:To analyze the indications for prenatal diagnosis and summarize the pregnancy outcomes and its influencing factors of pregnant women with fetal sex chromosome aneuploidy (SCA).Methods:This study retrospectively enrolled 1 372 fetuses prenatally diagnosed with SCA in Medical Genetics Center of Guangdong Women and Children Hospital from January 2013 to December 2021. The relationship between prenatal diagnosis indications and SCA as well as between ultrasound abnormalities, pregnancy outcomes and SCA types were analyzed by Chi-square test and trend Chi-square test. Results:The most common prenatal diagnosis indication was abnormal non-invasive prenatal testing (NIPT) (61.6%, 845/1 372). The most common SCA type was 47,XXY in cases with indications of abnormal NIPT and advanced maternal age, mosaic in cases with high or borderline risk of Down syndrome, and 45,X in cases with increased nuchal translucency or cystic hygroma. Of 1 372 pregnant women with fetal SCA, 17 were lost to follow-up, seven had intrauterine fetal death, and 1 348 (98.3%) were followed up for pregnancy outcomes including 36.3% (489/1 348) continued pregnancies and 63.7% (859/1 348) terminations. Pregnancy termination rates decreased sequentially in pregnant women carrying fetuses with 45,X, 47,XXY, mosaic, 47,XXX and 47,XYY [99.2% (247/249), 74.5% (307/412), 67.8% (156/230), 36.6% (86/235) and 28.4% (63/222), χ2trend=352.76, P<0.001]. There was no significant difference in pregnancy termination rates among the cases with different mosaic mutations (all P>0.05). The pregnancy termination rate was higher in fetuses with SCA complicated by ultrasound structural abnormalities than in those without ultrasound abnormalities and those with ultrasound soft markers [91.5% (182/199) vs 57.1% (535/937) and 67.0% (142/212), χ2 were 83.68 and 36.85, both P<0.001]. Moreover, the pregnancy termination rate in fetuses with SCA complicated by ultrasound soft markers was higher than those without ultrasound abnormalities ( χ2=7.13, P<0.05). Conclusions:NIPT abnormality is the most common indication for prenatal diagnosis of SCA. The types of SCA and ultrasound findings are important factors determining whether the pregnancy would be continued or not.

Genetic analysis of 387 cases of fetal sex chromosome abnormalities detected from amniotic fluid samples / 中华围产医学杂志

Objective:To analyze fetal sex chromosome abnormalities in prenatal diagnosis based on amniotic fluid cell culture.Methods:Clinical data of 12 164 pregnant women who underwent amniocentesis in Maternal and Child Health Hospital of Hunan Province from January 2017 to December 2020 were retrospectively analyzed. For those diagnosed with fetal sex chromosome abnormalities, the results of karyotyping and chromosome microarray analysis (CMA) were analyzed and described.Results:(1) Among the 12 164 cases, fetal sex chromosome abnormalities were detected in 387 cases (3.2%), including 351 cases with abnormal sex chromosome karyotype and 36 with sex chromosome microdeletion/microduplication. (2) High-risk patients indicated by non-invasive prenatal test (NIPT) had the highest proportion of sex chromosomes abnormalities (74.2%, 287/387), followed by those with other ultrasound abnormalities (8.5%, 33/387), high risk of Down syndrome screening (7.0%, 27/387), advanced maternal age (4.7%, 18/387), history of adverse pregnant or delivery (3.3%, 13/387), and nuchal translucency thickening or cervical lymphatic hygroma (2.3%, 9/387). (3) Detected chromosome karyotype abnormalities included numerical abnormalities [73.2%(257/351)], mosaicism [18.8(66/351)], and structural abnormalities [8.0%(28/351)], among which, 47,XXY [46.7%(120/257)], 45,X/46,XX[48.5%(32/66)], and X chromosome deletion [39.3%(11/28)] were the most common, respectively. Among 36 sex chromosome microdeletions/microduplications cases, 15(41.7%) were with pathogenic copy number variation (CNV), including 14 cases of X chromosome microdeletion/microduplication; 7(19.4%) with benign CNV, and 14(38.9%) with CNV of unknown clinical significance. The fragment size [ M (min-max)] of the 15 pathogenic CNV was 1.68 Mb(0.37-9.20 Mb). Of the nine cases with microdeletions, seven were found with deletion in the Xp22.31 region. Conclusions:Numerical abnormalities are the most common fetal sex chromosome abnormalities detected from amniotic fluid samples. Others included mosaicism and chromosome structure abnormalities.

45,X/46,XY Mosaicism in an 18-year-old girl with primary Amenorrhea: A case report / Journal of the ASEAN Federation of Endocrine Societies

@#45,X/46,XY mosaicism is a rare disorder with a wide heterogeneity in its manifestations. An 18-year-old girl was referred to the endocrine clinic for investigation of her primary amenorrhea. Clinical examination was unremarkable. Hormonal profile was consistent with primary ovarian insufficiency and human chorionic gonadotropin (hCG) stimulation did not show evidence of active testicular tissue. Karyotyping studies by G-banding revealed a 45,X/46,XY karyotype. She was diagnosed with mosaic Turner syndrome with Y chromosomal material and investigation was performed to identify the presence of male gonads due to the risk of gonadal malignancy. Magnetic resonance imaging (MRI) of the pelvis did not show evidence of gonads. Laparoscopic exploration was proposed but the patient and parents refused opting for conservative management. This case highlights the challenges in the management of this rare condition.

Cellular and molecular genetic analysis of sex chromosome chimerism and dicentric isochromosome structural abnormalities: a report of two cases / 中华围产医学杂志

Objective@#To investigate the value of karyotype analysis, bacterial artificial chromosomes-on-beads (BoBs), chromosome microarray analysis (CMA) and fluorescence in situ hybridization (FISH) in the diagnosis of sex chromosome numerical and structural abnormalities.@*Methods@#Conventional G-banding staining technique was used to analyze the karyotypes of amniotic fluid cells and parental peripheral blood cells in two pregnancies with prenatal diagnosis indications. Sex chromosome numerical and structural abnormalities were analyzed based on the results of G-banding, BoBs, CMA and FISH.@*Results@#The results of G-banding karyotype analysis showed that there were mosaics in amniotic fluid cells collected from both cases. Karyotype of Case A was 45,X[25]/46,X,idic(Y)(q11.2?)[6], and Case B was 45,X[39]/46,X,psu idic(X)(q21.32?)[44]. Parental peripheral blood karyotypes of both families were normal. Prenatal BoBs indicated copy number abnormalities in sex chromosomes (Y chromosome in Case A and X chromosome in Case B). CMA results suggested a 20.1 Mb duplication in Yp11.32q11.222, and a 7.7 Mb deletion in Yq11.222q11.23 in fetus A with possible karyotype of 46,X,idic(Y)(q11.222); for fetus B, a 92.0 Mb duplication in Xp22.33q21.32, and a 63.0 Mb deletion in Xq21.32q28 were detected, and the karyotype might be 46,X,psu idic(X)(q21.32). The mid-term FISH test of amniotic fluid cells showed that 90% of the amniotic cells from Case A were 45,X, and 10% were 46,X,idic(Y)(q11.2); about 38% were 45,X, and 62% were 46,X,psu dic(X)(q21.3) from Case B.@*Conclusions@#Numerical and structural abnormalities of sex chromosomes could be accurately diagnosed by combination of several methods including G-banding karyotype analysis, prenatal BoBs, CMA and FISH, which would help to effectively reduce birth defects.

Sex chromosome aneuploidy screened by non-invasive prenatal testing from 35827 singletons: prenatal diagnosis and pregnancy determinations / 中华围产医学杂志

Objective To assess the positive predictive value (PPV) of fetal sex chromosome aneuploidy (SCA) identified by non-invasive prenatal testing (NIPT) and investigate families' acceptance of SCA fetus. Methods All suspected SCA cases screened by NIPT from singletons were reviewed in Prenatal Diagnosis Center of Shanghai First Maternity and Infant Hospital from April 1, 2015 to October 31, 2017. Maternal age, NIPT indications, prenatal diagnosis protocols, testing results and their pregnancy determinations were analyzed. Results NIPT was provided to 35827 singletons and 86 suspected SCA cases were identified out of 35823 successful ones, giving a positive detection rate of 0.24％. The average maternal age was (31.5±5.0) years. After genetic counseling, 20 patients declined prenatal diagnosis,the rest 66 cases proceeded with aminiocentesis and fetal chromosomal testing, of which 32 were cytogenetically diagnosed as SCA with the PPV of 48.5％ . The SCA fetus consisted of 25 sex chromosome trisomies (seven cases of 47,XXX, three cases of 47,XYY and 15 cases of 47,XXY), one monosomy X (45,X), three mosacisms (47,XXY/48,XXYY, 47,XXX/45,X, 45,X/46,XX, one for each) and three microdeletions/microduplications. Besides, two false positive NIPT cases were proved to be low level of maternal mosacism (45,X/46,XX, 5％ and 10％ for each). After genetic counseling, 17 out of 20 who declined prenatal diagnosis and 9 out of 32 who diagnosed fetal SCAs continued their pregnancies, with a combined proportion of continued pregnancy of 50％. Thirty-four pregnancies were also continued after exclusion of SCA. Interestingly, the proportion of continued pregnancy among those sex chromosomal trisomy fetuses was only 32％(8/25). Conclusions As a safe and rapid prenatal testing for common autosomal aneuploidies, NIPT could also identify some types of SCA, but with relatively low PPV. More long-term researches are required to determine its sensitivity and specificity. For some types of SCA with mild phenotypes, some family would continue the pregnancy. Therefore, limitations of NIPT should be appropriately explained during both pre- and post-testing counseling.

Prenatal diagnosis of an unbalanced translocation between chromosome Y and chromosome 15 in a female fetus

We report the prenatal diagnosis of an unbalanced translocation between chromosome Y and chromosome 15 in a female fetus. Cytogenetic analysis of parental chromosomes revealed that the mother had a normal 46,XX karyotype, whereas the father exhibited a 46,XY,der(15)t(Y;15) karyotype. We performed cytogenetic analysis of the father's family as a result of the father and confirmed the same karyotype in his mother and brother. Fluorescence in situ hybridization and quantitative fluorescent-polymerase chain reaction analysis identified the breakpoint and demonstrated the absence of the SRY gene in female members. Thus, the proband inherited this translocation from the father and grandmother. This makes the prediction of the fetal phenotype possible through assessing the grandmother. Therefore, we suggest that conventional cytogenetic and molecular cytogenetic methods, in combination with family history, provide informative results for prenatal diagnosis and prenatal genetic counseling.

Noninvasive prenatal test for the pregnancy with Turner syndrome mosaicism 45, X/47, XXX: A case report

Noninvasive prenatal test (NIPT) is a novel screening method for the diagnosis of fetal chromosomal aneuploidies. NIPT is based on technology that detects cell-free fetal DNA in maternal plasma and analyzes it with massively parallel sequencing technology to determine whether the fetus is at risk of trisomy 21, trisomy 18, trisomy 13 or sex chromosome abnormalities (SCAs). NIPT has been reported to have sensitivity of 99% and a false positive rate of less than 1% for detecting trisomy 21 and trisomy 18. Although extension of the application of NIPT to other SCAs has been attempted, there are concerns in extending NIPT to SCAs because of maternal or fetal mosaicism, undetected maternal SCAs, and multiple pregnancies. Recently, we assessed a pregnancy with the rare Turner syndrome mosaicism 45, X/47, XXX, which was reported as 45, X with NIPT. We present the case here and briefly review the current literatures on NIPT in testing for fetal monosomy X. To the best of our knowledge, this is the first report of the 45, X/47, XXX mosaicism in Korea to be reported as 45, X by NIPT with whole genome sequencing. This case report will provide valuable information for counseling women who want to undergo NIPT.

Resultados en el diagnóstico prenatal citogenético en Pinar del Río / Results of the Prenatal Cytogenetic Diagnosis in Pinar del Río

Introducción: el Diagnóstico Prenatal Citogenético utilizando las células del líquido amniótico, constituye, la principal modalidad en Cuba para realizar los estudios cromosómicos prenatales en aquellas embarazadas con riesgos de tener un niño afectado. Ojetivo: describir las principales alteraciones cromosómicas detectadas en el diagnostico prenatal citogenético en la Provincia de Pinar del Río a partir de enero del año 2007 hasta Diciembre del 2012. Material y método: se realizó un estudio descriptivo, retrospectivo en 2777 pacientes que fueron remitidos al Centro Provincial de Genética Médica para estudios prenatales. Los datos recopilados fueron: motivos de indicación, número y tipo de aberraciones cromosómicas detectadas y embarazadas con un diagnóstico prenatal de defectos congénitos que decidieron continuar el embarazo. Resultados: durante esta etapa se realizaron un total de 2777 estudios cromosómicos prenatales; el motivo de indicación que más prevaleció fue la avanzada edad materna (75.62 % del total de los casos). Se diagnosticaron un total de 43 fetos con anomalías cromosómicas, incluyendo 28 casos con aneuploidías, 12 con reordenamientos estructurales y 3 mosaicos cromosómicos. Conclusiones: se trabajó con los criterios técnicos y diagnósticos establecidos internacionalmente para este tipo de estudios, el por ciento de positividad fue de 1.54 y los resultados obtenidos fueron similares a los reportados por otros estudios.

Introduction: the Cytogenetic Prenatal Diagnosis using amniotic liquid cells contitutes the main resource in Cuba to carry out cromosomal studies in pregnant women with risk of having an afected baby. Objective: to describe main chromosomal disorders detected in the cytogenetic prenatal diagnosis in Pinar del Río Province from January 2007 to December 2012. Material and method: a descriptive, retrospective study was carried out of 2,777 patients referred to the Province Center of Medical Genetics for prenatal studies. Compiled data were: referral causes, number and types of detected chromosomal disorders, and pregnant women with a prenatal diagnosis of congenital malformations, who decided for complete gestation. Results: during that period a sheer number of 2,777 prenatal chromosomal studies were carried out. The prevalent referral cause was advanced maternal age (75.62% of all cases). A total of 43 fetuses with chromosomal abnormalities, including 28 cases with aneuploidies, 12 with structural reorderings and 3 chromosomal mosaics. Conclusions: the work was done under diagnostical and technical internationally established criteria for these types of studies, the positiveness percentage was 1.54 and the results obtained were similar to those reported by other studies.

Parental Decisions of Prenatally Detected Sex Chromosome Abnormality

Because of the widespread use of amniocentesis, the prenatal recognition of sex chromosome abnormality (SCA) has become increasingly common. Recent literature provided an insight into the understanding of the natural history and prognosis for individuals with SCA. Our study was designed to review the parental decision on pregnancy with SCA. Over the last 10 yr, we diagnosed 38 cases (0.50%) with SCA out of 7,498 prenatal cases. We reviewed the records and the results of the pregnancies. We included the cases (n=25) of apparently normal anatomic fetus to analyze the factors influencing parental decision. We excluded 13 cases with obvious anomaly or presumably bad outcome. Fifteen (60%) couples continued their pregnancies and ten (40%) terminated theirs. Nine couples (64%) out of fourteen mosaicism cases continued their pregnancies. All five pregnancies assisted by reproductive technique continued their pregnancies. More pregnancies were continued when counseling was done by an MD geneticist rather than by an obstetrician. A significant trend was observed with a higher rate of pregnancy continuation in recent years. The genetic counseling is important to give appropriate information to the parents. Establishing guidelines and protocols will help both obstetricians and parents to make a decision.