Prenatal diagnosis of trisomy 3 mosaicism

OBJECTIVES: To present the clinical, cytogenetic, and molecular cytogenetic findings of prenatally diagnosed trisomy 3 mosaicism. CASE AND METHODS: Trisomy 3 mosaicism is rare, and only two cases of prenatally diagnosed trisomy 3 mosaicism have been reported. Amniocentesis, performed for AMA, revealed a karyotype of 47,XX, + 3[8]/46,XX[27]. Periumbilical blood sampling (PUBS) showed 46,XX in 100 cells. Fluorescence in situ hybridization (FISH) analysis using an alpha satellite chromosome 3 probe confirmed the cytogenetic findings. A repeat amniocentesis confirmed mosaicism for trisomy 3 (47,XX, + 3[1]/46,XX[18]). The infant was delivered by elective C-section because of the presence of IUGR and oligohydramnios. The baby had normal physical findings at birth except for symmetric IUGR, apparently resulting from the placental trisomic cell lines. At delivery, chromosome analysis of 50 cells each from blood, placenta, and umbilical cord revealed 46,XX in all cells. FISH analysis of amniotic fluid cells (54 nuclei), peripheral blood (50 nuclei), umbilical cord fibroblasts (57 nuclei), and placental tissue (52 nuclei) demonstrated two signals in 200 nuclei (i.e., 46,XX) and three signals in 13 nuclei (i.e., 47,XX, + 3). At 11 months of age, the baby was progressing normally. CONCLUSION: A diagnosis of trisomy 3 mosaicism is problematic for patients and clinicians. This is only the third case of trisomy 3 mosaicism identified at amniocentesis. Ultrasound, PUBS, and evaluation of placental tissues and postnatal peripheral blood, were useful in providing information regarding the fetal involvement of trisomy 3. Additional cases of prenatally diagnosed mosaicism for rare trisomies are necessary to more accurately assess the significance of these findings.     

Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic trisomy 15 at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of mosaic trisomy 15 in a pregnancy with a favorable outcome.Case reportA 33-year-old, primigravid woman underwent amniocentesis at 19 weeks of gestation because non-invasive prenatal testing (NIPT) revealed gene dosage increase at chromosome 15. Cytogenetic analysis revealed a karyotype of 47,XX,+15[10]/46,XX[13]. Using uncultured amniocytes, array comparative genomic hybridization (aCGH) revealed arr [GRCh37] (X) × 2, (15) × 3 [0.75], multiplex ligation-dependent probe amplification (MLPA) analysis showed rsa [GRCh36] 15q11q13 (21,362,818–27,196,819) × 3 [0.76] and methylation-specific (MS)-MLPA analysis showed a methylation index = 0.41 with paternal gene dosage increase at 15q11-q13. Repeat amniocentesis at 25 weeks of gestation revealed a karyotype of 47,XX,+15[6]/46,XX[14]. Using uncultured amniocytes, quantitative fluorescent polymerase chain reaction (QF-PCR) assays excluded uniparental disomy (UPD) 15 and determined a paternal origin of the extra chromosome 15, aCGH analysis showed 75%–80% mosaicism for trisomy 15, and interphase fluorescence in situ hybridization (FISH) showed 45.5% (46/101 cells) mosaicism for trisomy 15. Repeat amniocentesis at 28 weeks of gestation revealed a karyotype of 47,XX,+15[2]/46,XX[23]. Using uncultured amniocytes, aCGH showed 75–80% mosaicism for trisomy 15, and FISH showed 70.6% (72/102 cells) mosaicism for trisomy 15. Using cultured amniocytes, QF-PCR assays excluded UPD 15. Cordocentesis at 30 weeks of gestation revealed a karyotype of 47,XX,+15[2]/46,XX[138]. Using cord blood, aCGH revealed 9% gene dosage increase at chromosome 15, and MS-MLPA analysis excluded UPD 15. At 36 weeks of gestation, a 2060-g phenotypically normal baby was delivered. The cord blood had 46, XX (40/40 cells). The placenta had 47,XX,+15 (40/40 cells). QF-PCR analysis on placenta showed a paternal origin of trisomy 15. FISH analysis on buccal mucosal cells at age 20 days showed 20% (20/100 cells) mosaicism for trisomy 15.ConclusionCytogenetic discrepancy may occur between uncultured and cultured amniocytes in mosaic trisomy 15 at amniocentesis. Cultured amniocytes may present progressive decrease in the levels of mosaicism for trisomy 15 as the fetus grows. Mosaic trisomy 15 at amniocentesis without UPD 15 can be associated with a favorable outcome.     

Low-level mosaicism for trisomy 16 at amniocentesis in a pregnancy associated with intrauterine growth restriction and a favorable outcome

ObjectiveWe present low-level mosaicism for trisomy 16 at amniocentesis in a pregnancy associated with intrauterine growth restriction (IUGR) and a favorable outcome.Case reportA 31-year-old woman underwent amniocentesis at 24 weeks of gestation because of IUGR. Amniocentesis revealed a karyotype of 47,XX,+16 [3]/46,XX [22]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed gene dosage increase in chromosome 16 consistent with 28% mosaicism for trisomy 16. Uniparental disomy (UPD) 7 and UPD 11 were excluded. She underwent repeat amniocentesis at 27 weeks of gestation. Repeat amniocentesis revealed a karyotype of 47,XX,+16 [1]/46,XX [24]. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed 25%–35% (log₂ ratio = 0.17–0.25) mosaicism for trisomy 16. Interphase fluorescence in situ hybridization (FISH) analysis detected trisomy 16 signals in 28/100 (28%) uncultured amniocytes. Polymorphic DNA marker analysis excluded UPD 16. Level II ultrasound revealed no fetal abnormalities except symmetric IUGR. The pregnancy was continued to 37 weeks of gestation, and a 2306-g phenotypically normal baby was delivered. The cord blood had a karyotype of 46, XX in 50/50 lymphocytes. The umbilical cord had a karyotype of 47,XX,+16 [14]/46,XX [36]. Interphase FISH analysis on buccal mucosal cells and urinary cells at age three days revealed trisomy 16 signals in 3.8% (4/106) buccal mucosal cells and 6.5% (7/107) urinary cells, compared with 1% in the normal control. Polymorphic DNA marker analysis on placenta confirmed trisomy 16 in the placenta and a maternal origin of the extra chromosome 16.ConclusionCytogenetic discrepancy between cultured amniocytes and uncultured amniocytes may present in mosaic trisomy 16 at amniocentesis. Low-level mosaicism for trisomy 16 at amniocentesis without maternal UPD 16 can be associated with a favorable outcome despite the presence of IUGR.     

Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic trisomy 18 at amniocentesis in a pregnancy with a favorable fetal outcome and maternal uniparental disomy 18

ObjectiveWe present prenatal diagnosis of mosaic trisomy 18 in a pregnancy with a favorable fetal outcome and maternal uniparental disomy 18.Case reportA 38-year-old, primigravid woman underwent the first amniocentesis at 16 weeks of gestation because advanced maternal age. Amniocentesis revealed a karyotype of 46,XX [22/22] in cultured amniocytes, and 36% mosaicism for trisomy 18 and a maternally inherited Xp22.31 microdeletion by array comparative genomic hybridization (aCGH) in uncultured amniocytes. The second amniocentesis at 18 weeks of gestation revealed 47,XX,+18 [14]/46,XX [36] in cultured amniocytes and 36% mosaicism for trisomy 18 by multiplex ligation-dependent probe amplification (MLPA) P095 in cultured amniocytes. Prenatal ultrasound was normal. The parents were phenotypically normal. The third amniocentesis at 23 weeks of gestation revealed 47,XX,+18 [3]/46,XX [17] in cultured amniocytes, and in uncultured amniocytes, aCGH revealed 45%–50% mosaicism for trisomy 18, interphase fluorescence in situ hybridization (FISH) revealed 36% (36/100 cells) mosaicism for trisomy 18, and quantitative fluorescent polymerase chain reaction (QF-PCR) showed mosaic maternal uniparental heterodisomy for chromosome 18 and mosaic trisomy 18 of maternal origin. The fourth amniocentesis at 32 weeks of gestation revealed a karyotype of 46,XX [20/20] in cultured amniocytes, and in uncultured amniocytes, aCGH revealed 50%–60% mosaicism for trisomy 18, FISH revealed 21.8% (22/101 cells) mosaicism for trisomy 18, and non-invasive prenatal testing (NIPT) showed chromosome 18 gene dosage increase in the maternal blood. At 34 weeks of gestation, a 1480-g phenotypically normal baby was delivered. The cord blood had 47,XX,+18 [10]/46,XX [30]. The umbilical cord had 47,XX,+18 [4]/46,XX [36]. The placenta had 47,XX,+18 [40/40], and QF-PCR analysis confirmed trisomy 18 of maternal origin. When follow-up at age four months, the neonate was phenotypically normal, FISH analysis on buccal mucosal cells revealed 2% (2/100 cells) mosaicism for trisomy 18, and the peripheral blood had 47,XX,+18 [18]/46,XX [22]. When follow-up at age eight months, the neonate had normal development, the peripheral blood had 47,XX,+18 [15]/46,XX [25], and the buccal mucosal cells showed maternal uniparental heterodisomy for chromosome 18.ConclusionCytogenetic discrepancy may occur between uncultured and cultured amniocytes in mosaic trisomy 18 at amniocentesis. Cultured amniocytes may present progressive decrease in the levels of mosaicism for trisomy 18 as the fetus grows. Mosaic trisomy 18 at amniocentesis can be associated with a favorable outcome.     

Mosaic trisomy 2 at amniocentesis: Prenatal diagnosis and molecular genetic analysis

ObjectiveThis study aims at presenting prenatal diagnosis of mosaic trisomy 2 and reviewing the literature.Materials, Methods, and ResultsA 32-year-old woman underwent amniocentesis at 21 weeks of gestation because of abnormal maternal serum biochemistry. Amniocentesis revealed a karyotype of 47,XY,+2[1]/46,XY[21] in in situ cultures. The single colony with trisomy 2 had two metaphase cells, and both had the karyotype of 47,XY,+2. Repeated amniocentesis was performed at 23 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes using a 2q11.1-specific probe RP11-468G5 (spectrum green) showed three green signals in 11 of 47 uncultured amniocytes, indicating 23.4% mosaicism for trisomy 2. The cultured amniocytes had a karyotype of 46,XY[20 colonies]. Polymorphic DNA marker analysis excluded uniparental disomy 2. The woman underwent the third amniocentesis at 25 weeks of gestation. Interphase FISH analysis on uncultured amniocytes revealed 9.4% (5/53 cells) mosaicism for trisomy 2. The cultured amniocytes had a karyotype of 46,XY[30 colonies]. Prenatal ultrasound was normal. The parents decided to continue the pregnancy to term, and a 3316-g baby was delivered with no phenotypic abnormalities. Cord blood had a karyotype of 46,XY[40 cells]. Interphase FISH analysis on uncultured urinary cells revealed 8.2% (4/49 cells) mosaicism for trisomy 2. The neonate was normal in growth and psychomotor development at 6 months of age.ConclusionPrenatal diagnosis of a single colony with two or more cells with trisomy 2 at amniocentesis should alert a clinically significant aneuploidy, and interphase FISH on uncultured amniocytes is useful for rapid confirmation of low-level trisomy 2 mosaicism at amniocentesis. The abnormal cell line of trisomy 2 may disappear after long-term amniocyte cultures.     

Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes in mosaic double trisomy involving trisomy 7 and trisomy 20 (48,XY,+7,+20) at amniocentesis

ObjectiveWe present mosaic double trisomy involving trisomy 7 and trisomy 20 at amniocentesis in a pregnancy with a favorable outcome.Case reportA 41-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a result of 48,XY,+7,+20[6]/46,XY[26] in cultured amniocytes. At 19 weeks of gestation, repeat amniocentesis was performed, which revealed a result of 48,XY,+7,+20[4]/46,XY[21] in cultured amniocytes. Simultaneous molecular cytogenetic analyses on uncultured amniocytes at repeat amniocentesis revealed no genomic imbalance in array comparative genomic hybridization (aCGH) analysis, no trisomy 7 and no trisomy 20 signals in 114/114 cells in interphase fluorescence in situ hybridization (FISH) analysis, and no uniparental disomy (UPD) 7 and no UPD 20 in quantitative fluorescent polymerase chain reaction (QF-PCR) analysis. Interphase FISH analysis on cultured amniocytes revealed double trisomy of trisomy 7 and trisomy 20 in 5/105 cells (4.7%) compared with 0/100 cells (0%) in the normal control. Prenatal ultrasound findings were unremarkable. The parental karyotypes were normal. The woman decided to continue the pregnancy, and a healthy 2880-g phenotypically normal male baby was delivered at 34 weeks of gestation without any structural abnormality. The cord blood had a normal karyotype. Interphase FISH analysis of the urinary cells revealed no trisomy 7 and no trisomy 20 signals in 51/51 urinary cells.ConclusionCytogenetic discrepancy between cultured amniocytes and uncultured amniocytes can occur in mosaicism for double trisomy involving trisomy 7 and trisomy 20 at amniocentesis. Molecular cytogenetic analyses such as aCGH, FISH and QF-PCR on uncultured amniocytes are useful for rapid distinguishing true mosaicism from pseudomosaicism under such a circumstance.     

Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic trisomy 15 at amniocentesis

ObjectiveWe present mosaic trisomy 15 at amniocentesis.Materials and methodsA 41-year-old woman underwent amniocentesis at 16 weeks of gestation because of an abnormal non-invasive prenatal testing (NIPT) result suspicious of trisomy 15. Amniocentesis revealed a karyotype of 46,XY. Array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed 26% mosaicism for trisomy 15. She was referred for repeat amniocentesis. aCGH, interphase fluorescence in situ hybridization (FISH), quantitative fluorescent polymerase chain reaction (QF-PCR) assays and/or conventional cytogenetic analysis were applied on various cells and tissues including uncultured amniocytes, cultured amniocytes, cord blood, placenta, parental bloods and/or buccal mucosal cells.ResultsRepeat amniocentesis at 21 weeks of gestation revealed a karyotype of 46, XY in cultured amniocytes, and 30% mosaicism for trisomy 15 by aCGH and 32% mosaicism for trisomy 15 by FISH in uncultured amniocytes. Repeat amniocentesis at 29 weeks of gestation revealed a karyotype of 46, XY in cultured amniocytes, and 15% mosaicism for trisomy 15 by aCGH and 7.2% mosaicism for trisomy 15 by FISH in uncultured amniocytes. QF-PCR on cultured amniocytes excluded uniparental disomy (UPD) 15. A phenotypically normal baby was delivered subsequently with a karyotype of 46, XY in cord blood and 2% mosaicism for trisomy 15 by FISH in buccal mucosal cells. The aCGH analysis revealed trisomy 15 in placenta and no genomic imbalance in cord blood. QF-PCR assays determined a maternal origin of trisomy 15 in placenta.ConclusionCytogenetic discrepancy may occur between uncultured and cultured amniocytes in mosaic trisomy 15 at amniocentesis. The cells of trisomy 15 cell line in prenatally detected mosaic trisomy 15 may decrease in number as the fetus grows. Whenever NIPT suspects trisomy 15, a confirmatory amniocentesis should include genetic analysis on both uncultured and cultured amniocytes to exclude mosaic trisomy 15 and maternal UPD 15, especially when the cultured amniocytes have a normal karyotype.     

Mosaic trisomy 12 at amniocentesis: Prenatal diagnosis and molecular genetic analysis

ObjectiveThis study is aimed at prenatal diagnosis of mosaic trisomy 12 and reviewing the literature.Materials and MethodsA 34-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX,+12[9]/46,XX[14]. She was referred to the hospital for genetic counseling. Repeated amniocentesis was performed at 22 weeks of gestation. Array comparative genomic hybridization (aCGH), interphase fluorescence in situ hybridization (FISH) and quantitative fluorescent polymerase chain reaction (QF-PCR) were applied on uncultured amniocytes, and conventional cytogenetic analysis was applied on cultured amniocytes.ResultsThe aCGH analysis on uncultured amniocytes revealed a small genomic gain in chromosome 12. Interphase FISH analysis on uncultured amniocytes using a 12q11-q12-specific probe of RP11-496H24 (green spectrum) showed three green signals in 17.8% (8/45 cells) of uncultured amniocytes. QF-PCR analysis on uncultured amniocytes using chromosome 12-specific microsatellite markers excluded uniparental disomy 12. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX,+12[5]/46,XX[25]. The parents decided to continue the pregnancy. A healthy 3270 g female baby was delivered at 39 weeks of gestation, with no phenotypic abnormalities. Cytogenetic analysis of the cord blood revealed a karyotype of 46,XX in 40/40 cultured lymphocytes. The neonate was normal in growth and psychomotor development at 6 months of age. Interphase FISH analysis on uncultured urinary cells revealed 5% (1/20 cells) mosaicism for trisomy 12.ConclusionPrenatal diagnosis of mosaic trisomy 12 at amniocentesis should alert a clinically significant aneuploidy. Interphase FISH and aCGH on uncultured amniocytes are useful for rapid confirmation of low-level trisomy 12 mosaicism at repeated amniocentesis.     

Mosaic trisomy 22 at amniocentesis: Prenatal diagnosis and literature review

ObjectiveWe present prenatal diagnosis of mosaic trisomy 22 at amniocentesis in a pregnancy with facial cleft, oligohydramnios and intrauterine growth restriction (IUGR), and we review the literature.Case reportA 37-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+22[9]/46,XX[9]. Array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes showed a result of arr(22) × 3 [0.8]. Prenatal ultrasound revealed fetal median facial cleft, oligohydramnios and IUGR. Repeat amniocentesis at 22 weeks of gestation using uncultured amniocytes revealed an aCGH result of arr 22q11.1q13.33 (17,397,498–51,178,264) × 2.8 compatible with 80% mosaicism for trisomy 22, and a fluorescence in situ hybridization (FISH) result of mosaic trisomy 22 with trisomy 22 in 54/100 interphase cells. The cultured amniocytes at repeat amniocentesis had a karyotype of 47,XX,+22[12]/46,XX[8]. The parental karyotypes were normal. Polymorphic DNA marker analysis confirmed a maternal origin of the extra chromosome 22. The pregnancy was terminated, and a 256-g female fetus was delivered with facial dysmorphism and median facial cleft. Cytogenetic analysis of the skin fibroblasts revealed a karyotype of 47,XX,+22[33]/46,XX[7].ConclusionFetuses with high level mosaicism for trisomy 22 at amniocentesis may present IUGR, facial cleft and oligohydramnios on prenatal ultrasound.     

Mosaic trisomy 18 at amniocentesis associated with a favorable fetal outcome in a pregnancy

ObjectiveWe present prenatal diagnosis of mosaic trisomy 18 by amniocentesis associated with a favorable fetal outcome in a pregnancy.Case reportA 42-year-old, gravida 4, para 2, woman underwent amniocentesis at 18 weeks of gestation because advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+18[6]/46,XX[17]. Simultaneous array comparative genomic hybridization (aCGH) on uncultured amniocytes showed the result of 45% mosaicism for trisomy 18. At 25 weeks of gestation, the woman underwent repeat amniocentesis which revealed a karyotype of 47,XX,+18[10]/46,XX[24]. Simultaneous aCGH on uncultured amniocytes showed the result of arr 18p11.32q23 (148,963–78,012,829) × 2.3 [GRCh (hg19)] with a log₂ ratio of 0.2–0.25 compatible with 30–38% mosaicism for trisomy 18. The parental karyotypes were normal. Prenatal ultrasound was unremarkable. Interphase fluorescence in situ hybridization (FISH) on uncultured amniocytes showed 27% (27/100 cells) mosaicism for trisomy 18. Quantitative fluorescent polymerase chain reaction (QF-PCR) on uncultured amniocytes excluded uniparental disomy (UPD) 18. Non-invasive prenatal testing (NIPT) analysis at 34 weeks of gestation revealed a significant gene dosage increase of chromosome 18 (29.95; normal control: ?3.0–3.0). At 39 weeks of gestation, a 2840-g phenotypically normal baby was delivered. The cord blood had a karyotype of 47,XX,+18[8]/46,XX[32]. The placenta was trisomy 18 of maternal origin. The umbilical cord had a karyotype of 47,XX,+18[2]/46,XX[38]. At age 1½ months, the peripheral blood had a karyotype of 47,XX,+18[5]/46,XX[35], and FISH analysis on buccal mucosal cells revealed 2% (2/102 cells) mosaicism for trisomy 18. When follow-up at age seven months, the neonate was phenotypically normal, and the peripheral blood had a karyotype of 47,XX,+18[1]/46,XX[39].ConclusionsMosaic trisomy 18 at amniocentesis without abnormal fetal ultrasound can be associated with a favorable outcome, and the abnormal trisomy 18 cell line may decrease progressively after birth.     

Low-level mosaic trisomy 9 at amniocentesis associated with a positive non-invasive prenatal testing for trisomy 9, maternal uniparental disomy 9, intrauterine growth restriction and a favorable fetal outcome in a pregnancy

ObjectiveWe present low-level mosaic trisomy 9 at amniocentesis associated with a positive non-invasive prenatal testing (NIPT) for trisomy 9, maternal uniparental disomy (UPD) 9, intrauterine growth restriction (IUGR) and a favorable fetal outcome in a pregnancy.Case reportA 41-year-old, gravida 3, para 0, woman underwent amniocentesis at 18 weeks of gestation because of NIPT at 10 weeks of gestation suspicious of trisomy 9 in the fetus. This pregnancy was conceived by in vitro fertilization (IVF). Amniocentesis revealed a karyotype of 47,XY,+9 [2]/46,XY[23]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1–22) × 2, (X,Y) × 1 and detected no genomic imbalance. Polymorphic DNA marker analysis showed maternal uniparental heterodisomy 9 in the amniocytes. Prenatal ultrasound was normal. The woman was referred for genetic counseling at 22 weeks of gestation. The soluble fms-like tyrosine kinase (sFlt)/placental growth factor (PlGF) = 13.1 (normal < 38). There was no gestational hypertension. Continuing the pregnancy was advised. No repeat amniocentesis was performed because of persistent irregular contractions. IUGR was noted. A 2156-g phenotypically normal baby was delivered at 37 weeks of gestation. The cord blood and umbilical cord had a karyotype of 46,XY (40/40 cells). The placenta had a karyotype of 47,XY,+9 (40/40 cells). The parental karyotypes were normal. Quantitative fluorescence polymerase chain reaction (QF-PCR) on the DNA extracted from parental bloods, cord blood, umbilical cord and placenta revealed maternal uniparental heterodisomy 9 in cord blood and umbilical cord, and trisomy 9 of maternal origin in placenta. When follow-up at age three months, the neonate was normal in development and phenotype. The buccal mucosal cells had 3% (3/101 cells) mosaicism for trisomy 9 by interphase fluorescent in situ hybridization (FISH) analysis.ConclusionMosaic trisomy 9 at prenatal diagnosis should alert the possibility of UPD 9 and include a UPD 9 testing. Low-level mosaic trisomy 9 at amniocentesis can be associated with UPD 9 and a favorable fetal outcome.     

Prenatal diagnosis of mosaicism for trisomy 11 in a single colony at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of mosaicism for trisomy 11 in a single colony at amniocentesis with a favorable outcome.Case ReportA 34-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a result of 47,XY,+11[1]/46,XY[9]. In 10 colonies of cultured amniocytes, all five cells in one colony had a karyotype of trisomy 11, while the rest nine colonies had a normal karyotype. The parental karyotypes were normal. Repeat amniocentesis was performed at 19 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) was applied on the uncultured amniocytes, and the result showed no trisomy 11 signals in 56/56 uncultured amniocytes. Uniparental disomy (UPD) 11 was excluded by polymorphic DNA marker analysis. The cultured amniocytes at repeat amniocentesis had a karyotype of 46,XY. Prenatal ultrasound findings were unremarkable. A healthy 3084-g male baby was delivered at 38 weeks of gestation. The karyotype of cord blood lymphocytes was 46,XY. The boy was phenotypically normal at age 10 months at follow-ups. The interphase FISH analysis on urinary cells revealed no trisomy 11 signal.ConclusionMosaicism for trisomy 11 in a single colony at amniocentesis without UPD 11 can be associated with a favorable outcome.     

Prenatal diagnosis of low-level mosaicism for trisomy 21 by amniocentesis in a pregnancy associated with maternal uniparental disomy of chromosome 21 in the fetus and a favorable outcome

ObjectiveWe present perinatal molecular cytogenetic analysis of low-level mosaicism for trisomy 21 in a pregnancy with maternal uniparental disomy (UPD) of chromosome 21 in the fetus.Case reportA 39-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+21[6]/46,XX[25]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (21) × 2–3, (X) × 2 with about 18% gene dosage increase in chromosome 21 consistent with mosaic trisomy 21. Cordocentesis was performed at 20 weeks of gestation, and the cord blood lymphocytes had a karyotype of 47,XX,+21[3]/46,XX[72]. Prenatal ultrasound findings were unremarkable. After genetic counseling, the parents decided to continue the pregnancy. At 39 weeks of gestation, a 3,494-g phenotypically normal female baby was delivered without phenotypic features of Down syndrome. There was no dysplasia of middle phalanx of the fifth fingers of both hands. The cord blood had a karyotype of 47,XX,+21[2]/46,XX[48]. The placenta had a karyotype of 47,XX,+21[37]/46,XX[3]. The umbilical cord had a karyotype of 47,XX,+21[1]/46,XX[39]. aCGH analysis on the DNA extracted from cord blood revealed no genomic imbalance. Polymorphic DNA marker analysis on the DNAs extracted from cord blood and parental bloods revealed maternal uniparental heterodisomy 21 in the baby. Interphase fluorescence in situ hybridization analysis on buccal mucosal cells revealed trisomy 21 signals in 15/101 (14.9%) buccal cells at birth and in 1/122 (0.82%) buccal cells at age 45 days.ConclusionLow-level mosaicism for trisomy 21 at amniocentesis associated with maternal UPD 21 in the fetus can have a favorable outcome.     

Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes in mosaic trisomy 20 at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present our observation of cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes in mosaic trisomy 20 at amniocentesis in a pregnancy with a favorable outcome.Case reportA 35-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+20[10]/46,XX[15]. Among 25 colonies of cultured amniocytes, 10 colonies had a karyotype of 47,XX,+20, while the rest were normal. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed no genomic imbalance, or arr (1–22,X) × 2. The parental karyotypes were normal. Following genetic counseling, the woman underwent repeat amniocentesis at 20 weeks of gestation. Repeat amniocentesis revealed a karyotype of 47,XX,+20[3]/46,XX[35]. Among 38 colonies of cultured amniocytes, three colonies had a karyotype of 47,XX,+20, while the rest were normal. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed no genomic imbalance, or arr (1–22,X) × 2. Interphase fluorescence in situ hybridization analysis on 101 uncultured amniocytes detected only one cell with three chromosome 20 signals with a mosaic trisomy 20 level of 1% (1/101 cells), compared with 0% in normal control. Polymorphic DNA marker analysis on the DNA extracted from uncultured amniocytes and parental bloods excluded uniparental disomy 20. At 38 weeks of gestation, a phenotypically normal 3120-g female baby was delivered. Cytogenetic analysis of cord blood, placental tissue and umbilical cord revealed a karyotype of 46,XX. The neonate was normal at postnatal follow-ups. Postnatal interphase fluorescence in situ hybridization analysis on 100 buccal mucosal cells revealed no trisomy 20 signals.ConclusionMosaic trisomy 20 at amniocentesis can be a cultured artifact. Complete cytogenetic discrepancy may occur between cultured amniocytes and uncultured amniocytes in mosaic trisomy 20 at amniocentesis, and molecular cytogenetic analysis on uncultured amniocytes is useful for rapid distinguishing true mosaicism from pseudomosaicism under such as circumstance.     

A case of maternal uniparental disomy of chromosome 9 diagnosed prenatally and the related problem of residual trisomy

Non-mosaic trisomy 9 was found in a chorionic villus (CV) sample taken from a 43-year-old woman referred for prenatal chromosome analysis due to advanced maternal age. Follow-up amniocentesis revealed level 2 mosaicism for trisomy 9. Trisomy 9 was not detected at fetal blood sampling. Molecular analysis of fetal (amniocyte) DNA showed maternal uniparental heterodisomy (UPD) for chromosome 9. Two crossovers resulted in a region of isodisomy in the distal long arm. Trisomy rescue of a meiosis 1 segregation error seems to have been responsible for the uniparental disomy of chromosome 9. The pregnancy continued and neonatal blood testing showed a mosaic trisomy 9 karyotype, i.e. 4/50 cells analysed. Clinical postnatal follow-up for a period of 1 year has documented only minor facial dysmorphism and skeletal abnormalities. Development appears unremarkable. This case is the second report of maternal uniparental disomy for chromosome 9 detected prenatally and is the first case followed up post-term. This report highlights the difficulty of making informed prognostic assessments in such cases despite extensive laboratory investigation.     

Prenatal diagnosis of mosaic trisomy 8: clinical report and literature review

ObjectiveTo present prenatal diagnosis of mosaic trisomy 8 and to review the literature.Materials, Methods, and ResultsA 34-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+8[6]/46,XY[31]. Repeated amniocentesis at 21 weeks of gestation revealed a karyotype of 47,XY,+8[4]/46,XY[77]. Interphase fluorescence in situ hybridization analysis of uncultured amniocytes showed 25% (5/20) mosaicism for trisomy 8. Array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) analyses of uncultured amniocytes revealed no genomic imbalance in chromosome 8. The result of QF-PCR excluded uniparental disomy 8. At 23 weeks of gestation, the woman underwent amniocentesis and cordocentesis at other hospitals. Amniocentesis revealed a karyotype of 47,XY,+8[6]/46,XY[10]. Cordocentesis revealed a karyotype of 47,XY,+8[1]/46,XY[29]. Level II ultrasound findings were unremarkable. The parents decided to continue the pregnancy. A 1373-g male baby was prematurely delivered at 29 weeks of gestation. The peripheral blood had a karyotype of 47,XY,+8[1]/46,XY[29]. The infant had normal growth and mental development at 4 months of age.ConclusionFetuses with mosaic trisomy 8 are compatible with viability and can have a favorable outcome. QF-PCR and array comparative genomic hybridization have the limitation of detection of low-level mosaicism. We suggest that in instances of repeated amniocentesis for confirmation of mosaic trisomy 8, follow-up investigations should include interphase fluorescence in situ hybridization studies on uncultured amniocytes, uniparental disomy tests, and detailed ultrasound examinations.     

Prenatal diagnosis of mosaicism for double aneuploidy of 47,XXY and trisomy 7 (48,XXY,+7) at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of mosaicism for double aneuploidy of 47, XXY and trisomy 7 (48,XXY,+7) at amniocentesis in a pregnancy with a favorable outcome.Case reportA 33-year-old woman underwent amniocentesis at 17 weeks of gestation because of an increased risk for Down syndrome in maternal serum screening. Amniocentesis revealed a karyotype of 48,XXY,+7[8]/46,XY[16]. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr [GRCh37] (7) × 3 [0.54], (X) × 2 [0.52], (Y) × 1, compatible with trisomy 7 mosaicism and Klinefelter syndrome mosaicism. The parental karyotypes and prenatal ultrasound findings were normal. Repeat amniocentesis performed at 23 weeks of gestation revealed a karyotype of 48,XXY,+7[13]/46,XY[7]. Simultaneous molecular cytogenetic analyses on uncultured amniocytes revealed 30% mosaicism for 48,XXY,+7 by aCGH and 37% (37/100 cells) mosaicism for trisomy 7 and disomy X by interphase fluorescence in situ hybridization (FISH) analysis. Polymorphic DNA marker analysis excluded uniparental disomy (UPD) 7 and indicated a maternal origin of the chromosome aberration. The pregnancy was continued to 39 weeks of gestation, and a 3070-g healthy male baby was delivered. The cord blood had a karyotype of 46,XY, the umbilical cord had a karyotype of 48,XXY,+7[3]/46,XY[37], and the placenta had a karyotype of 48,XXY,+7. At age one month, the neonate was phenotypically normal, and interphase FISH analysis revealed 4.8% (5/105 cells) mosaicism on buccal mucosal cells and 8.9% (8/90 cells) mosaicism on urinary cells for trisomy 7 and disomy X, compared with 2% in normal control. Interphase FISH analysis on buccal mucosal cells at age two months revealed normal findings in 100/100 cells.ConclusionMosaic 48,XXY,+7 at amniocentesis without UPD 7 can be associated with a favorable fetal outcome. Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes may occur in mosaic 48,XXY,+7 at amniocentesis.     

Low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with a favorable fetal outcome,intrauterine growth restriction,cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes and perinatal progressive decrease of the aneuploid cell line

ObjectiveWe present low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with a favorable fetal outcome, intrauterine growth restriction (IUGR), cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes and perinatal progressive decrease of the aneuploid cell line.Case reportA 37-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. This pregnancy was conceived by in vitro fertilization and embryo transfer (IVF-ET). Amniocentesis revealed a karyotype of 47,XY,+9[11]/46,XY[32], and simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (X,Y) × 1, (1–22) × 2 without genomic imbalance. Prenatal ultrasound and parental karyotypes were normal. Repeat amniocentesis at 22 weeks of gestation revealed a karyotype of 47,XY,+9[5]/46,XY[19], and simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed arr 9p24.3q34.3 × 2.1 (log₂ ratio = 0.1) compatible with 10–15% mosaicism for trisomy 9. Quantitative fluorescence polymerase chain reaction (QF-PCR) assays excluded uniparental disomy (UPD) 9. A third amniocentesis at 29 weeks of gestation revealed a karyotype of 47,XY,+9[5]/46,XY[18], and simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed arr 9p24.3q34.3 × 2.1 (log₂ ratio = 0.1) compatible with 10–15% mosaicism for trisomy 9. Interphase fluorescent in situ hybridization (FISH) analysis on uncultured amniocytes revealed 9% (9/100 cells) mosaicism for trisomy 9. IUGR was noted on prenatal ultrasound. The pregnancy was carried to 38 weeks of gestation, and a 2375-g phenotypically normal male baby was delivered. The karyotypes of umbilical cord, cord blood and placenta were 46,XY (40/40 cells), 47,XY,+9[1]/46,XY[39] and 47,XY,+9[12]/46,XY[28], respectively. QF-PCR assays on placenta showed trisomy 9 of maternal origin. When follow-up at age two months, the neonate was normal in development. The peripheral blood had a karyotype of 46,XY (40/40 cells), and the buccal mucosal cells had 7.5% (8/106 cells) mosaicism for trisomy 9 by interphase FISH analysis.ConclusionLow-level mosaic trisomy 9 at amniocentesis can be associated with a favorable fetal outcome and cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes.     

Detection of maternal uniparental disomy 9 in association with low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with intrauterine growth restriction,abnormal first-trimester screening result (low PAPP-A and low PlGF), maternal preeclampsia and a favorable outcome

ObjectiveWe present detection of maternal uniparental disomy (UPD) 9 in association with low-level mosaic trisomy 9 at amniocentesis in a pregnancy associated with intrauterine growth restriction (IUGR), an abnormal first-trimester maternal serum screening result, abnormal non-invasive prenatal testing (NIPT), maternal preeclampsia and a favorable outcome.Case reportA 37-year-old, primigravid woman underwent first-trimester maternal serum screening and NIPT at 11 weeks of gestation, which revealed a gene dosage increase in chromosome 9 and low levels of plasma protein-A (PAPP-A) and placental growth factor (PlGF) in maternal blood. The woman underwent amniocentesis at 16 weeks of gestation, which revealed a karyotype of 47,XX,+9[4]/46,XX[35] in cultured amniocytes. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed a result of arr [GRCh37] (9) × 3 [0.14] (X) × 2, compatible with mosaic trisomy 9. The parental karyotypes were normal. Repeat amniocentesis was performed at 20 weeks of gestation. The cultured amniocytes had a karyotype of 47,XX,+9[1]/46,XX[23]. The uncultured amniocytes had a mosaic trisomy 9 level of 10.7% (12/112 cells) by interphase fluorescence in situ hybridization (FISH), a mosaic trisomy 9 level of 10–14% (log₂ ratio = 0.1) by aCGH, and maternal uniparental isodisomy 9 by polymorphic DNA marker analysis. Prenatal ultrasound revealed IUGR, and the mother had preeclampsia. At 29 weeks of gestation, a 1054-g phenotypically normal baby was delivered because of preterm labor. The cord blood and umbilical cord had the karyotype of 46, XX and maternal UPD 9 and isodisomy 9, while the placenta had trisomy 9 of maternal origin. Postnatal FISH anlaysis on 101 buccal mucosal cells and 100 urinary cells at age three months detected no trisomy 9 signals. The baby was doing well at age six months.ConclusionPregnancy with low-level mosaic trisomy 9 and maternal UPD 9 at amniocentesis can be associated with IUGR, maternal preeclampsia and a favorable outcome. Fetuses with maternal UPD 9 can be associated with an abnormal NIPT result concerning chromosome 9, an abnormal first-trimester maternal serum screening result (low PAPP-A and low PlGF) and mosaic trisomy 9 at amniocentesis.     

Prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome

Objective

We present prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome.