Prenatal diagnosis of a familial normal euchromatic variant of dup(15)(q11.2q11.2) in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of a familial normal euchromatic variant of dup(15)(q11.2q11.2) in a pregnancy with a favorable outcome.Case reportA 32-year-old woman underwent elective amniocentesis at 17 weeks of gestation because of anxiety. Amniocentesis revealed a karyotype of 46,XX,dup(15)(q11.2q11.2). Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (1–22, X) × 2 with no genomic imbalance. Cytogenetic analysis of the parental bloods showed that the mother had a karyotype of 46,XX,dup(15)(q11.2q11.2), and the father had a karyotype of 46,XY. Prenatal ultrasound findings were unremarkable. A healthy 2948 g female baby was delivered at 39 weeks of gestation without any phenotypic abnormality. Cytogenetic analysis of the cord blood revealed a karyotype of 46,XX,dup(15)(q11.2q11.2).ConclusionPrenatal diagnosis of dup(15)(q11.2q11.2) should include a differential diagnosis of a 15q11.2 (BP1-BP2) microduplication encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1, and aCGH analysis is useful for the differential diagnosis under such a circumstance.     

Prenatal diagnosis and molecular cytogenetic characterization of partial dup (18p)/del (18q) due to a maternal pericentric inversion 18 in a foetus with multiple anomalies

ObjectiveThe 18q terminal deletion with inverted duplication is an extremely rare abnormality, with only three confirmed cases in Europe to date. Here, we report, for the first time, a case of de novo 18q inv-dup-del in a Turkish pregnant woman.Case reportA 30-year-old pregnant woman was referred for genetic analysis at her 25th gestational week due to foetal diaphragmatic hernia and rocker bottom feet. Cytogenetic analysis of the parents revealed a karyotype of 46,XX,inv(18) (p11.3q21.3) of the mother and a normal karyotype of the father. The foetal karyotype was defined as 46,XX,rec(18)del(18q)inv(18) (p11.3q21.3)mat.ConclusionTo our knowledge, this is the first report of a prenatal diagnosis. Genetic counselling issues for this family, particularly affected individuals, include an increased likelihood of reduced fertility and a risk of recurrence of parental inversion equal to 1/2 in surviving offspring.     

Prenatal diagnosis of holoprosencephaly (HPE) in a fetus with a recombinant (18)dup(18q)inv(18)(p11.31q11.2)mat

Alobar holoprosencephaly (HPE) was identified by ultrasonography at 18 weeks' gestation in a fetus of a 29-year-old G2P0A1 woman. HPE has been described in association with various chromosomal anomalies. Amniocentesis was performed and a rearrangement of chromosome 18 resembling an isochromosome for the long arm of chromosome 18 was found. Subsequently, the mother was found to have a pericentric inversion of chromosome 18 with breakpoints at p11.31 and q11.2. The karyotype of the fetus was re-interpreted as 46,XX, rec(18)dup(18q)inv(18)(p11.31q11.2)mat. This is the first case of a parental inversion leading to a deficiency of 18p11.31 to 18pter associated with HPE.     

Prenatal diagnosis and molecular cytogenetic characterization of a derivative chromosome der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3) presenting as apparent isochromosome 18q in a fetus with holoprosencephaly

ObjectiveTo present prenatal diagnosis and molecular cytogenetic characterization of a derivative chromosome der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3).Materials, Methods, and ResultsA 32-year-old woman was referred for genetic counseling of prenatally detected isochromosome 18q [i(18q)]. She had undergone amniocentesis at 19 gestational weeks because of a trisomy 18 risk of 1/39 derived from abnormally low levels of maternal serum unconjugated estriol, inhibin A, α-fetoprotein, and total β-human chorionic gonadotropin. Amniocentesis revealed a karyotype of 46,XX,i(18)(q10). Parental karyotypes were normal. Prenatal ultrasound showed alobar holoprosencephaly. Repeated amniocentesis was requested and performed at 21 gestational weeks. Array-comparative genomic hybridization analyses revealed a 14-Mb deletion of 18p11.32-p11.21, a 37.8-Mb duplication of 18q12.1-q22.1, and a 6.9-Mb duplication of 18q22.3-q23. Metaphase fluorescence in situ hybridization study showed the absence of an 18q12.1-specific probe signal in one arm and the absence of an 18q22.2-specific probe signal in the other arm of the derivative chromosome. Quantitative fluorescent polymerase chain reaction analysis determined a paternal origin of the derivative chromosome. The cytogenetic result was 46,XX,der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3). The fetus postnatally manifested cebocephaly.ConclusionConcomitant monosomy 18p and trisomy 18q can be associated with holoprosencephaly and abnormal maternal serum screening results. Array-comparative genomic hybridization, fluorescence in situ hybridization, and quantitative fluorescent polymerase chain reaction are useful in genetic counseling of prenatally detected isochromosomes by providing information on the origin and genetic components of the isochromosome.     

Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes in mosaic 46,XX,dup(9)(q22.3q34.1)/46,XX at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present our observation of cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes in mosaic dup(9)(q22.3q34.1) at amniocentesis in a pregnancy with a favorable outcome.Case reportA 37-year-old, gravida 4, para 0, woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XX, dup(9)(q22.3q34.1)[8]/46,XX[16]. Prenatal ultrasound findings were unremarkable. She was referred for genetic counseling, and repeat amniocentesis was performed at 21 weeks of gestation, which revealed a karyotype of 46,XX,dup(9)(q22.3q34.1)[7]/46,XX[25]. Simultaneous array comparative genomic hybridization (aCGH) on the DNA extracted from uncultured amniocytes revealed no genomic imbalance, or arr (1–22,X) × 2. Interphase fluorescence in situ hybridization (FISH) analysis on 105 uncultured amniocytes detected only one cell with the dup 9q signal with a mosaic dup 9q level of 1%, compared with 0% in normal control. At 37 weeks of gestation, a 2640-g female baby was delivered with no phenotypic abnormality. The cord blood had a karyotype of 46,XX,dup(9) (q22.3q34.1)[4]/46,XX[36], the umbilical cord had a karyotype of 46,XX,dup(9) (q22.3q34.1)[2]/46,XX[38], and the placenta had a karyotype of 46,XX. aCGH analysis on cord blood revealed no genomic imbalance. At age 2½ months, the baby was doing well, the peripheral blood of the baby had a karyotype of 46,XX,dup(9) (q22.3q34.1)[4]/46,XX[36], and interphase FISH analysis on buccal mucosal cells revealed no dup 9q signal in 100 buccal mucosal cells.ConclusionCytogenetic discrepancy may occur between cultured amniocytes and uncultured amniocytes in mosaic dup(9) (q22.3q34.1). Molecular cytogenetic analysis on uncultured amniocytes is useful for rapid distinguishing pseudomosaicism from true mosaicism under such a circumstance.     

Fetoplacental discrepancy involving structural abnormalities of chromosome 8 detected by prenatal diagnosis

We describe the finding of three cell lines involving different structural abnormalities of chromosome 8 detected in a prenatal diagnosis. Chorionic villi sampling (CVS) was performed on a pregnant woman because of advanced maternal age. Semidirect cytogenetic analysis showed a mos46,XX,i(8q)/46,XX,del(8)(p11.2) karyotype, confirmed by fluorescence in situ hybridization (FISH). Amniocentesis was subsequently performed, and the karyotype obtained was 46,XX,dup(8)(p23p11.2). The pregnancy was terminated; pathologic findings included clubfeet, clenched left hand, subcutaneous edema and bilateral hydrocephalus. Molecular studies using chromosome 8 microsatellites performed on parents' blood and fetal tissues revealed a maternal meiotic origin of the inv dup(8p) with deletion of the distal p23 region and duplication of the remaining 8p. We propose a model to explain the cytogenetic findings, which includes a first maternal meiotic error giving rise to a large dicentric isochromosome 8 present in the ovum, a second error in one of the first zygote divisions with misdivision of the dicentric 8 giving rise to a cell line with del(8p) confined to the trophoblast and another cell line with inv dup(8p) confined to the fetal tissue and a third error in the trophoblast giving rise to a further cell line with isochromosome 8q.     

Molecular cytogenetic characterization of del(X)(p22.33)mat and de novo dup(4)(q34.3q35.2) in a male fetus with multiple anomalies of facial dysmorphism,ventriculomegaly, congenital heart defects,short long bones and clinodactyly

ObjectiveWe present molecular cytogenetic characterization of del(X) (p22.33)mat and de novo dup(4) (q34.3q35.2) in a male fetus with multiple anomalies of facial dysmorphism, ventriculomegaly, congenital heart defects, short long bones and clinodactyly.Case reportA 36-year-old, gravida 3, para 1, woman with short stature (152 cm) underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,Y,del(X)(p22.33)mat, dup(4)(q34.3q35.2). The mother had a karyotype of 46,X,del(X)(p22.33). Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed arr Xp22.33 × 0, 4q34.3q35.2 × 3. Prenatal ultrasound at 23 weeks of gestation revealed multiple anomalies of flat nasal bridge, ventriculomegaly, atrioventricular septal defect (AVSD) and clinodactyly. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Cytogenetic analysis of the umbilical cord revealed 46,Y,del(X)(p22.33)mat, dup(4)(q34.3q35.2)dn. aCGH analysis on the DNA extracted from the umbilical cord revealed arr [GRCh37 (hg19)] 4q34.3q35.2 (181,149,823–188,191,938) × 3.0, arr Xp22.33 (470,485–2,985,006) × 0 with a 7.042-Mb duplication of 4q34.3-q35.2 and a 2.514-Mb deletion of Xp22.33.ConclusionA male fetus with del(X)(p22.33) and dup(4)(q34.3q35.2) may present congenital heart defects and short long bones on prenatal ultrasound.     

Two unusual chromosome aberrations ascertained by sonographic anomalies

We describe two cases of sonographic abnormalities associated with unusual chromosomal aberrations. Case 1 presented with a cystic hygroma at 12 weeks' gestation. Cytogenetic analysis revealed an unbalanced complex chromosome rearrangement implicating chromosomes 6, 13 and 21 (karyotype: 47,XX,t(6;21;14)(q14;q21;q21)mat,+21) and corresponding to a complete trisomy 21. This anomaly resulted from malsegregation of a maternal balanced three-way translocation. For case 2, an alobar holoprosencephaly was identified by ultrasonography at 23 weeks' gestation. Chromosomal analysis showed a recombinant rec (13), dup q chromosome, secondary to unequal crossing-over of a paternal pericentric inversion of chromosome 13, giving rise to partial trisomy 13q (karyotype: 46,XX,rec(13)dup(13q)inv(13)(p11q21)pat). These two cases illustrate the role of ultrasound in leading to detection not only of foetal chromosomal aberrations but also of rare balanced chromosomal rearrangements presented by one of the two parents.     

Mosaic Xq duplication,or 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)/ 46,XX at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present mosaic Xq duplication, or 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)/46,XX at amniocentesis in a pregnancy with a favorable outcome.Case ReportA 40-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a result of 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)[7]/46,XX[20]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (1–22, X) × 2. Cytogenetic analysis on maternal blood revealed a karyotype of 46,XX. At 22 weeks of gestation, she underwent repeat amniocentesis which revealed a karyotype of 46,XX in 22/22 colonies of cultured amniocytes and an aCGH result of (1–22, X) × 2 in the uncultured amniocytes. Prenatal ultrasound findings were unremarkable. The parents decided to continue the pregnancy, and a healthy female baby was delivered at 39 weeks of gestation with a body weight of 3510 g and a body length of 49 cm. The cord blood had a karyotype of 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)[3]/46,XX[37]. At age two months, interphase fluorescence in situ hybridization (FISH) analysis on buccal mucosal cells showed Xq duplication signals in 1.25% (1/80 cells), compared with 0% (0/90 cells) in the normal control. At age nine months, the neonate had normal physical and psychomotor development. Her body weight was 9.6 Kg (85th - 97th centile), and body length was 72 cm (50th - 85th centile). Cytogenetic analysis of peripheral blood revealed a karyotype of 46,X,der(X)dup(X) (q22.1q22.2)dup(X)(q25q22.3)[1]/46,XX[39]. Interphase FISH analysis on 100 buccal mucosal cells revealed no abnormal signal.ConclusionIn case of mosaicism for an Xq duplication with a normal euploid cell line at amniocentesis, the in-vitro culture process of amniocytes may cause over-estimation of the mosaic level for the aberrant chromosome because of culture artifacts, and the abnormal cell line can decline after birth.     

Prenatal diagnosis of partial monosomy 8p (8p23.2→pter) and partial trisomy 15q (15q21.2→qter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency and an abnormal maternal serum screening result

ObjectiveWe present partial monosomy 8p (8p23.2→pter) and partial trisomy 15q (15q21.2→qter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency (NT) and an abnormal maternal serum screening result.Case ReportA 29-year-old primigravid woman underwent chorionic villus sampling (CVS) at 13 weeks of gestation because of an increased NT thickness of 3.2 mm at 12 weeks of gestation and an abnormal maternal serum screening for Down syndrome result with a calculated risk of 1/29. Her husband was 33 years old, and there was no family history of congenital malformations. CVS revealed a derived chromosome 8 or der(8). Cytogenetic analysis of the parents revealed a karyotype of 46,XY,t(8;15)(p21.3;q13) in the father and a karyotype of 46,XX in the mother. The CVS result was 46,XY,der(8)t(8;15)(p21.3;q13)pat. The woman requested for amniocentesis at 16 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a result of arr 8p23.3p23.2 (191,530–2,625,470) × 1.0, arr 15q21.2q26.3 (50,903,432–102,338,129) × 3.0 with a 2.434-Mb deletion of 8p23.3-p23.2 including DLGAP2, CLN8 and ARHGEF10, and a 51.435-Mb duplication of 15q21.2-q26.3 including CYP19A1 and IGF1R. Conventional cytogenetic analysis of cultured amniocytes revealed the result of 46,XY,der(8) t(8;15)(p23.2;q21.2)pat in the fetus. The pregnancy was subsequently terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism.ConclusionMaternal serum screening and NT screening may incidentally detect familial unbalanced reciprocal translocations, and aCGH analysis is useful for a precise determination of the breakpoints of the translocation and the involvement of the related genes under such a circumstance.     

Prenatal diagnosis and molecular cytogenetic characterization of a pure ring chromosome 21 with a 4.657-Mb 21q22.3 deletion

ObjectiveWe present diagnosis and molecular cytogenetic characterization of a pure ring chromosome [r(21)] with a 4.657-Mb 21q22.3 deletion.Case reportA 44-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype 46,XX,r(21)(p11.2q22.3). Prenatal ultrasound findings were unremarkable. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed a 4.657-Mb deletion at 21q22.3. The parental karyotypes were normal. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism and clinodactyly. Postnatal cytogenetic analysis of umbilical cord revealed a karyotype of 46,XX,r(21)(p11.2q22.3). aCGH analysis of umbilical cord revealed the result of arr 21q22.3 (43,427,188–48,084,156) × 1.0 with a 4.657-Mb 21q22.3 deletion encompassing 57 Online Mendelian Inheritance in Man (OMIM) genes including TRPM2, TSPEAR, COL18A1, COL6A1, COL6A2, LSS, PCNT, DIP2A, S100B and PRMT2. Metaphase fluorescence in situ hybridization (FISH) analysis of the umbilical cord fibroblasts confirmed a 21q22.3 deletion.ConclusionPrenatal diagnosis of an r(21) should include molecular cytogenetic characterization such as aCGH and FISH to determine the extent of the 21q22.3 deletion.     

Prenatal diagnosis of partial monosomy 2q (2q37.3→qter) and partial trisomy 10q (10q24.31→qter) of paternal origin associated with increased nuchal translucency and abnormal maternal serum screening results

ObjectiveWe present prenatal diagnosis of terminal 2q deletion and distal 10q duplication of paternal origin in a fetus associated with increased nuchal translucency and abnormal maternal serum screening results.Case reportA 26-year-old woman who had experienced spontaneous abortion twice underwent amniocentesis at 16 weeks of gestation because of an increased nuchal translucency thickness of 3.5 mm at 12 weeks of gestation and abnormal maternal serum screening results of 2.573 multiples of the median (MoM) of free β-human chorionic gonadotrophin (β-hCG) and 1.536 MoM of pregnancy-associated plasma protein-A (PAPP-A) resulting in a trisomy 21 risk of 1:64. Amniocentesis revealed a derivative chromosome 2. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr [hg19] 2q37.3 (238,294,223–242,782,258) × 1, 10q24.31q26.3 (102,018,246–135,426,386) × 3. Cytogenetic analysis of parental bloods revealed a karyotype of 46,XX in the mother and a karyotype of 46,XY,t(2;10)(q37.3;q24.3) in the father. The fetal karyotype was 46,XX,der(2)t(2;10)(q37.3;q24.3)pat. The pregnancy was terminated at 20 weeks of gestation, and a malformed fetus was delivered with facial dysmorphism. Postnatal analysis of the cord blood confirmed the results of prenatal diagnosis. The fetus had a 4.693-Mb deletion of 2q37.3 encompassing the genes of HDAC4, KIF1A, PASK, HDLBP, FARP2 and D2HGDH, and a 33.34-Mb duplication of 10q24.31-q26.3 encompassing the gene of NFκB2.ConclusionFirst-trimester ultrasound and maternal serum biochemistry screening may help to identify an unexpected unbalanced familial translocation at prenatal diagnosis.     

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.     

Two unbalanced segregation products due to a maternal t(7;16)inv(16)

We report a prenatal case of a maternally inherited abnormal chromosome 16, originally interpreted as a pericentric inversion only, but after family studies re-interpreted as a pericentric inversion (16) accompanied by an unbalanced (7;16) translocation. Because of the inversion 16 and an elder son with developmental delay and craniofacial dysmorphic features, in the past karyotyped as 46,XY, the chromosomes 16 of the mother and son were carefully re-examined. Using a whole chromosome 16 paint and sub-telomere probes of 16p and 16q, the karyotype of the mother was shown to be 46,XX,inv(16)(p11.2q23.2).ish t(7;16)(q36;p13.3)inv(16). Subsequently one chromosome 16 of the elder son appeared to be a der(16)t(7;16)(q36;p13.3). This is probably the result of a meiotic crossover between the chromosomes 16 in the mother. The prenatal karyotype was finally interpreted as 46,XY,inv(16)(p11.2q23.2).ish der(16)t(7;16)(q36;p13.3)inv(16). This is the same cytogenetic imbalance as his elder brother: a partial trisomy of chromosome 7 (q36-->qter) and a partial monosomy of chromosome 16 (p13.3-->pter).     

Inv dup del(10q): identification by fluorescence in situ hybridization and array comparative genomic hybridization in a fetus with two concurrent chromosomal rearrangements

ObjectiveTo present molecular cytogenetic characterization of an inverted duplication with terminal deletion of 10q, or inv dup del(10q) in a fetus with two concurrent chromosomal rearrangements.Materials, Methods and ResultsA 39-year-old woman underwent amniocentesis at 20 weeks of gestation because of advanced maternal age. Amniocentesis revealed a der(10) with additional material at the end of the long arm of chromosome 10, a der(9) and a der(22). Parental karyotypes were normal. A de novo unbalanced complex chromosomal rearrangement (CCR) was diagnosed by conventional cytogenetics, but the breakpoints could not be defined. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Postnatal analysis of fetal tissues using spectral karyotyping, fluorescence in situ hybridization, multicolor banding, and array-comparative genomic hybridization identified an inv dup del(10q) with an inverted duplication of 10q25.1→q26.2 and a terminal deletion of 10q26.2→qter, and a balanced reciprocal translocation between chromosomes 9 and 22. Microsatellite analysis determined a paternal origin of the inv dup del(10q). The karyotype of the fetus was 46,XX,t(9;22)(p23;q13),der(10)del(10)(q26.2) dup(10)(q26.2q25.1)dn.ConclusionA de novo inv dup del(10q) can be associated with a concurrent de novo balanced reciprocal translocation and should be differentiated from an unbalanced CCR by molecular cytogenetic techniques.     

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 3

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 3.Case reportA 36-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+mar[6]/46,XX[18]. The mother's karyotype was 47,XX,+mar[4]/46,XX[46]. The father's karyotype was 46.XY. Array comparative genomic hybridization (aCGH) analysis of uncultured amniocytes revealed a result of arr 3q11.1q12.1 (93,575,285–98,956,687) × 2–3 [GRCh37 (hg19)]. Prenatal ultrasound findings were unremarkable. The parents elected to continue the pregnancy, and a 2470-g female baby was delivered at 37 weeks of gestation without phenotypic abnormalities. The cord blood had a karyotype of 47,XX,+mar[8]/46,XX[32]. aCGH analysis of cord blood revealed a result of arr 3q11.1q11.2 (93,649,973–97,137,764) × 2.4 [GRCh37 (hg19)] with a log2 ratio of 0.25 and a 30–40% mosaicism for 3.488-Mb dosage increase in 3q11.1-q11.2 encompassing four [Online Mendelian Inheritance in Man (OMIM)] genes of PROS1, ARL13B, NSUN3 and EPHA6. Metaphase fluorescence in situ hybridization (FISH) analysis confirmed 30% (6/20 cells) mosaicism for the sSMC(3) in the blood lymphocytes.ConclusionaCGH and FISH analyses are useful for perinatal investigation of a prenatally detected sSMC.     

Inv dup del(9p): prenatal diagnosis and molecular cytogenetic characterization by fluorescence in situ hybridization and array comparative genomic hybridization

ObjectiveTo present molecular cytogenetic characterization of prenatally detected inverted duplication and deletion of 9p, or inv dup del(9p).Materials, Methods, and ResultsA 35-year-old primigravid woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a derivative chromosome 9, or der(9) with additional material at the end of the short arm of one chromosome 9. Parental karyotypes were normal. Level II ultrasound showed ventriculomegaly and normal male external genitalia. Repeated amniocentesis was performed at 20 weeks of gestation. Array comparative genomic hybridization revealed a 0.70-Mb deletion at 9p24.3 and an 18.36-Mb duplication from 9p24.3 to 9p22.1. The distal 9p deletion encompassed the genes of DOCK8, ANKRD15, FOXD4, DMRT1, and DMRT3. Fluorescence in situ hybridization analysis using bacterial artificial chromosome clone probes specific for 9p confirmed that the der(9) was derived from the inv dup del(9p). The karyotype of the fetus was 46,XY,inv dup del(9)(:p22.1→p24.3::p24.3→qter)dn or 46,XY,der(9) del(9)(p24.3) inv dup(9)(p22.1p24.3)dn. Polymorphic DNA marker analysis determined a maternal origin of the inv dup del(9p). A 512-g male fetus was subsequently terminated at 22 weeks of gestation with facial dysmorphism. The fetus had normal male external genitalia without sex reversal.ConclusionFluorescence in situ hybridization and array comparative genomic hybridization are useful to determine the nature of a prenatally detected aberrant chromosome derived from the inv dup del. Male fetuses with inv dup del(9p) and haploinsufficiency of DMRT1 and DMRT3 may present normal male external genitalia without sex reversal.     

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from ring chromosome 2

ObjectiveTo present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from ring chromosome 2 [r(2)].Methods and ResultsA 35-year-old woman underwent amniocentesis at 17 weeks of gestation, because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in 11 of 23 colonies of cultured amniocytes. Repeated amniocenteses were made. The sSMC was characterized by array comparative genomic hybridization (aCGH), interphase fluorescence in situ hybridization (FISH) and quantitative fluorescent polymerase chain reaction (QF-PCR) on uncultured amniocytes. In uncultured amniocytes, aCGH showed a 39.49-Mb genomic gain in chromosome 2 encompassing 2q11.2→q21.2, interphase FISH revealed a mosaic level of 52% (52/100 cells), and QF-PCR manifested a diallelic pattern for chromosome 2, with gene dosage increase in the paternal allele of proximal 2q-specific DNA markers. In cultured amniocytes, the sSMC was characterized by metaphase FISH, spectral karyotyping (SKY) and multicolor banding (MCB) to contain the centromere and proximal 2q, and the karyotype was 47,XX,+r(2)(p11.1q21.2)[14]/46,XX[11]. The pregnancy was terminated. The fetus postnatally manifested facial dysmorphisms. Postnatal cytogenetic analyses revealed the karyotypes of 47,XX,+r(2)[12]/46,XX[28] in cord blood, 47,XX,+r(2)[7]/46,XX[33] in umbilical cord, 47,XX,+r(2)[13]/47,XX,+idic r(2)[3]/46,XX[24] in placenta and 47,XX,+r(2)[8]/47,XX,+idic r(2)[1]/46,XX[31] in amnion.ConclusionMolecular cytogenetic techniques such as aCGH, interphase FISH and QF-PCR on uncultured amniocytes, and SKY, MCB and metaphase FISH on cultured amniocytes are useful for characterization of the nature of a prenatally detected sSMC.     

Mosaic tetrasomy 9p at amniocentesis in a pregnancy associated with a favorable fetal outcome,perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissues

ObjectiveWe present mosaic tetrasomy 9p at amniocentesis in a pregnancy associated with a favorable fetal outcome, perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissue.Case reportA 33-year-old primigravid woman underwent elective amniocentesis at 18 weeks of gestation because of anxiety, and the karyotype of cultured amniocytes was 47,XX,+i (9) (p10)[20]/46,XX [55]. Cordocentesis was performed at 20 weeks of gestation, and the karyotype of cord blood was 47,XX,+i (9) (p10)[7]/46,XX [15]. She was referred for genetic counseling at 23 weeks of gestation, and repeat amniocentesis revealed a karyotype of 47,XX,+i (9) (p10)[1]/46,XX [16] with seven cells in one colony having tetrasomy 9p in cultured amniocytes, and in uncultured amniocytes, quantitative fluorescence polymerase chain reaction (QF-PCR) analysis excluded uniparental disomy (UPD) 9 and determined paternal origin of the extra i (9p), array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr 9p24.3p13.1 × 3.0 consistent with 50% mosaicism for tetrasomy 9p, and interphase fluorescence in situ hybridization (FISH) on uncultured amniocytes showed 22.6% (12/53 cells) mosaicism for tetrasomy 9p. A third amniocentesis at 27 weeks of gestation revealed a karyotype of 46, XX (10/10 colonies) in cultured amniocytes, and interphase FISH analysis on uncultured amniocytes revealed 20% (20/100 cells) mosaicism for tetrasomy 9p. The parental karyotypes and prenatal ultrasound were normal. At 39 weeks of gestation, a phenotypically normal 3388-g female baby was delivered. The karyotypes of cord blood, umbilical cord and placenta were 47,XX,+idic (9) (q12)[19]/46,XX [21] or 47,XX,+idic (9) (pter→q12:q12→pter)[19]/46,XX [21], 47,XX,+idic (9) (q12)[1]/46,XX [39] and 47,XX,+idic (9) (q12)[4]/46,XX [36], respectively. When follow-up at age two months, the neonate was phenotypically normal, the peripheral blood had a karyotype of 47,XX,+idic (9) (q12)[18]/46,XX [22], and interphase FISH analysis on 100 buccal mucosal cells revealed 1% (1/100 cells) mosaicism for tetrasomy 9p. When follow-up at age seven months, the neonate was phenotypically normal, and the peripheral blood had a karyotype of 47,XX,+idic(9)(q12)[14]/46,XX[26].ConclusionMosaic tetrasomy 9p at amniocentesis can be a transient and benign condition, and can be associated with a favorable fetal outcome and perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissue.     

Prenatal diagnosis of a 15q11.2-q14 deletion of paternal origin associated with increased nuchal translucency,mosaicism for de novo multiple unbalanced translocations involving 15q11-q14, 5qter, 15qter, 17pter and 3qter and Prader–Willi syndrome

ObjectiveWe present prenatal diagnosis of a 15q11.2-q14 deletion of paternal origin associated with increased nuchal translucency (NT), mosaicism for de novo multiple unbalanced translocations involving 15q11-q14, 5qter, 15qter, 17pter and 3qter, and Prader–Willi syndrome (PWS).Case reportA 32-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of an increased NT thickness of 5.6 mm and abnormal maternal serum screening results in the first trimester. The pregnancy was conceived by in vitro fertilization and embryo transfer. Amniocentesis revealed a karyotype of 45,XX,der(5)t(5;15)(q35;q14),-15 [16]/45,XX,-15,der(17)t(15;17)(q14;p13)[3]/45,XX,der(15)t(15;15)(q35;q14),-15[2]. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed the result of arr 15q11.2q14 (22,765,628–38,651,755) × 1.0 [GRCh37 (hg19)] with a 15.886-Mb 15q11.2-q14 deletion encompassing TUBGCP5, CYFIP1, NIPA2, NIPA1, SNRPN, SNURF, SNORD116-1, IPW, UBE3A, ACTC1 and MEIS2. The pregnancy was subsequently terminated, and a malformed fetus with facial dysmorphism was delivered. The cord blood had a karyotype of 45,XX,der(5)t(5;15)(q35;q14),-15[46]/45,XX,der(3)t(3;15) (q29;q14),-15[2]/45,XX,-15,der(17)t(15;17)(q14;p13)[2]. The placenta had a karyotype of 45,XX,der(5) t(5;15)(q35;q14),-15. Polymorphic DNA marker analysis confirmed a paternal origin of the proximal 15q deletion.ConclusionIncreased NT and abnormal maternal serum screening results may prenatally be associated with PWS. Chromosome 15 rearrangements in PWS include mosaicism for de novo multiple unbalanced translocations.