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 and postnatal characterization of Y chromosome structural anomalies by molecular cytogenetic analysis

We describe three cases in which we used fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and comparative genomic hybridization (CGH) to characterize Y chromosome structural anomalies, unidentifiable by conventional G-banding. Case 1 was a 46,X,+mar karyotype; FISH analysis revealed an entire marker chromosome highlighted after hybridization with the Y chromosome painting probe. The PCR study showed the presence of Y chromosome markers AMG and SY620 and the absence of SY143, SY254 and SY147. CGH results confirmed the loss of Yq11.2-qter. These results indicated the presence of a deletion: del(Y)(q11.2). Case 2 was a 45,X [14]/46,XY[86] karyotype with a very small Y chromosome. The PCR study showed the presence of Y chromosome markers SY620 and AMG, and the absence of SY143, SY254 and SY147. CGH results showed gain of Yq11.2-pter and loss of Yq11.2-q12. These results show the presence of a Yp isodicentric: idic(Y)(q11.2). Case 3 was a 45,X,inv(9)(p11q12)[30]/46,X,idic(Y)(p11.3?),inv(9)(p11q12)[70] karyotype. The FISH signal covered all the abnormal Y chromosome using a Y chromosome paint. The PCR study showed the presence of Y chromosome markers AMG, SY620, SY143, SY254 and SY147. CGH only showed gain of Yq11.2-qter. These results support the presence of an unbalanced (Y;Y) translocation. Our results show that the combined use of molecular and classical cytogenetic methods in clinical diagnosis may allow a better delineation of the chromosome regions implicated in specific clinical disorders.     

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.     

High-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line

ObjectiveWe present prenatal diagnosis of high-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line.Case reportA 36-year-old, gravida 4, para 3, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X[22]/46,X,idic(Y)(q11.2)[4]. Prenatal ultrasound was unremarkable, and the fetus had normal male external genitalia. Repeat amniocentesis was performed at 20 weeks of gestation, and the second amniocentesis revealed a karyotype of 45,X[24]/46,X,idic(Y)(q11.2)[3]. Simultaneous interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed that 60% (62/103 cells) were Y-deleted cells. After genetic counseling, the parents decided to continue the pregnancy, and a 3020-g male baby was delivered with a body length of 52 cm, normal male genital organs and no phenotypic abnormalities. The karyotypes of cord blood, umbilical cord and placenta were 45,X[20]/46,X,idic(Y)(q11.2)[20], 45,X[31]/46,X,idic(Y)(q11.2)[9] and 45,X[40], respectively. At age one month, FISH analysis on urinary cells and buccal mucosal cells revealed 11.5% (7/61 cells) and 13.6% (16/118 cells), respectively for mosaicism for the Y-deleted cells. At age five month, the karyotype of peripheral blood was 45,X[9]/46,X,idic(Y)(q11.2)[31]. FISH analysis on buccal mucosal cells showed no abnormal Y-deleted cell (0/101 cells). At age 11 month, the karyotype of peripheral blood was 45,X[5]/46,X,idic(Y)(q11.2)[35]. FISH analysis on 102 buccal mucosal cells showed no abnormal signals. The infant was doing well with normal physical and psychomotor development.ConclusionHigh-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis can be associated with a favorable outcome and progressive decrease of the 45,X cell line.     

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

ObjectiveWe present prenatal diagnosis of rec(18)dup(18q)inv(18)(p11.2q21.2)pat owing to paternal pericentric inversion in a fetus.Case reportA 37-year-old woman was diagnosed with multiple anomalies on a prenatal ultrasound scan at 17 weeks and 5 days of gestation. She underwent amniocentesis at 20 weeks and 2 days. Conventional karyotyping of amniocyte showed 46, XX, der(18). She was thus referred for genetic counseling; cytogenetic analysis revealed a 46, XY karyotype, inv(18)(p11.2q21.2), of the father. Therefore, based on the results of the father, the fetal karyotype was defined as 46, XX, rec(18)dup(18q)inv(18)(p11.2q21.2)pat. Array comparative genomic hybridization of amniocytes to obtain specific information showed a 3-Mb deletion of 18p11.31p11.32 (136227_3100353)x1 and a 23.7-Mb duplication of 18q21.31-q23 (54222717_77957375) × 3.ConclusionMaternal serum screening produces normal results for 18p-/18q+ syndrome, but it can be diagnosed by fluorescent in situ hybridization, quantitative-fluorescent polymerase chain reaction, or array comparative genomic hybridization test by observing abnormal findings on ultrasound.     

Mosaicism for Robertsonian jumping translocation at amniocentesis: 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY,genetic counseling,prenatal diagnosis and postnatal follow-up in a pregnancy with a favorable fetal outcome

ObjectiveWe present genetic counseling, prenatal diagnosis and postnatal follow-up of 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY at amniocentesis in a pregnancy with a favorable fetal outcome.Case reportA 27-year-old, primigravid woman underwent amniocentesis at 19 weeks of gestation because increased nuchal translucency thickness, and the result was 45,XY,der(15;22)(q10;q10)[29]/46,XY,i(15)(q10)[3]/46,XY[5]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1–22) × 2, (X,Y) × 1. The maternal karyotype was 45,XX,der(15;22)(q10;q10), and the paternal karyotype was 46,XY. She was referred for genetic counseling, and repeat amniocentesis performed at 23 weeks of gestation revealed 45,XY,der(15;22)(q10;q10)mat[23]/45,XY,-22[2]. aCGH analysis on uncultured amniocytes detected no genomic imbalance, and polymorphic DNA marker analysis excluded uniparental disomy (UPD) 15. Fluorescence in situ hybridization (FISH) analysis using the chromosome 15q specific probe and the chromosome 22q specific probe detected three 15q signals in 4/104 cells (3.8%). The woman was advised to continue the pregnancy, and, a 3186-g phenotypically normal male baby was delivered at 38 weeks of gestation. The umbilical cord had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells). When follow-up at age seven months, the neonate was normal in development, the peripheral blood had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells), and the buccal mucosal cells had normal signals in all 100 cells.ConclusionsMosaicism for Robertsonian jumping translocations at amniocentesis can be a transient condition and can be associated with a familial Robertsonian translocation and a favorable fetal outcome. Prenatal diagnosis of a Robertsonian jumping translocation involving chromosome 15 should include UPD 15 testing to exclude UPD 15.     

Molecular cytogenetic characterization of de novo concomitant proximal 21q deletion of 21q11.2q21.3 and distal Xp deletion of Xp22.33p22.2 due to an unbalanced X;21 translocation detected by amniocentesis

ObjectiveWe present molecular cytogenetic characterization of de novo concomitant proximal 21q deletion of 21q11.2q21.3 and distal Xp deletion of Xp22.33p22.2 due to an unbalanced X; 21 translocation detected by amniocentesis.Case reportA 35-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X,der(X)t(X; 21) (p22.2; q21.3),-21. Simultaneous array comparative genomic hybridization (aCGH) revealed the result of an 11.9-Mb Xp22.33p22.2 deletion encompassing HCCS, SHOX, AMELX and OFD1 and a 15.4-Mb 21q11.2q21.3 deletion encompassing NRIP1 and APP. The pregnancy was subsequently terminated, and a malformed fetus was delivered with craniofacial dysmorphism. The parental karyotypes were normal. Polymorphic DNA marker analysis by quantitative fluorescence polymerase chain reaction (QF-PCR) confirmed a paternal origin of the 21q proximal deletion. Cytogenetic analysis of cord blood confirmed the karyotype of 45,X,der(X)t(X; 21) (p22.2; q21.3),-21. aCGH analysis of the cord blood confirmed the prenatal diagnosis.ConclusionQF-PCR analysis is useful for determination of the parental origin of a de novo unbalanced X; autosome translocation detected by prenatal diagnosis. The information acquired is useful for genetic counseling under such a circumstance.     

Karyotype determination and reproductive guidance for short stature women with a hidden Y chromosome fragment

Two unrelated couples came to the Reproductive and Genetic Hospital of Citic-Xiangya to ask for reproductive guidance. One couple had an affected son and the other couple had secondary infertility. Conventional GTG banding showed that the women in both couples had a 46,X,add(X)(p22) karyotype. Further molecular cytogenetic studies showed that both women had a 46,X,der(X)t(X;Y)(p22;q11.2) karyotype and that the affected boy had inherited the derivative X chromosome, which resulted in an Xp contiguous gene syndrome. After an assessment of reproductive risk, the first couple conceived naturally and opted for prenatal diagnosis (PND) by amniocentesis. No abnormal karyotypes were found for the twin pregnancy and healthy twin girls were born after a full-term normal pregnancy. The second couple chose to undergo IVF with preimplantation genetic diagnosis (PGD). Two PGD cycles were performed by fluorescence in-situ hybridization. In the first PGD cycle, all three embryos had abnormal hybridization signals. In the second cycle, a male embryo with normal hybridization signals was transferred into the womb and a normal pregnancy was achieved. The results show the importance of detecting the derivative chromosome followed by PND or PGD if a woman carries an Xp;Yq translocation.Two unrelated couples came to our clinic to ask for reproductive guidance. The first couple had an affected son. Conventional GTG banding showed the woman carried a derivative metacentric X chromosome. Further molecular cytogenetic study identified this derivative X chromosome originated from a cryptic translocation between Xp and Yq and the karyotype of the woman was determined as 46,X,der(X)t(X;Y)(p22;q11.2), and the affected boy had inherited the derivative X chromosome, which resulted in an Xp contiguous gene syndrome. After assessment of reproductive risk, the couple conceived naturally. Prenatal diagnosis by amniocentesis showed a normal karyotype for the twin pregnancy and healthy twin girls were born at full term. The other couple was affected by secondary infertility. They chose to undergo IVF with preimplantation genetic diagnosis (PGD). Two PGD cycles was performed by fluorescence in-situ hybridization. In the second cycle, a male embryo with normal hybridization signals was transferred to the womb and a normal pregnancy was achieved. We emphasize the importance of identifying the hidden Y chromosome fragment to avoid the delivery of unbalanced offspring among women with a normal phenotype apart from short stature. This is the first report of the application of PGD for this unbalanced translocation 46,X,der(X)t(X;Y)(p22;q11.2).     

Prenatal diagnosis of a familial Y long-arm and chromosome 15 short-arm translocation inherited from a mother carrier

ObjectiveWe present prenatal diagnosis of a familial Y long-arm and chromosome 15 short-arm translocation inherited from a mother carrier.Case ReportA 34-year-old primigravid woman underwent amniocentesis at 20 weeks of gestation because of advanced maternal age. Amniocentesis revealed a derived chromosome 15 or 15p+ with an additional material on the short arm of chromosome 15. Cytogenetic analysis of the parents revealed that the phenotypically normal mother carried the same 15p+ variant, and the father had a karyotype of 46,XY. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed no genomic imbalance. Polymorphic DNA marker analysis using the DNAs extracted from cultured amniocytes and parental bloods excluded uniparental disomy (UPD) 15. C-banded preparations and metaphase fluorescence in situ hybridization analysis using a Yq12-specific probe showed a positive stain on the 15p+, indicating the origin of Yq on the short arm of the derivative chromosome 15. The karyotype of amniocentesis was 46,XX,der(15)t(Y;15)(q12;p13)mat. The mother had a karyotype of 46,XX,der(15) t(Y;15)(q12;p13). At 39 weeks of gestation, a 3006-g healthy female baby was delivered with no phenotypic abnormality. During follow-up at age six months, she manifested normal physical and psychomotor development.ConclusionPrenatal diagnosis of a 15p+ variant should include a differential diagnosis of genomic imbalance and UPD 15, and aCGH and polymorphic DNA marker analyses are useful under such a circumstance.     

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).     

Cytogenetical diagnosis in paraffin-embedded fetoplacental tissue using comparative genomic hybridization

Comparative genomic hybridization (CGH) is a FISH-related technique used to assess global chromosomal aberrations in a variety of human tumours. Recently CGH has been applied to cytogenetic analysis of fresh frozen fetoplacental tissues. Here we report the application of CGH to paraffin-embedded placental samples. Ten samples from paraffin-embedded blocks of 6 control placentas and fetoplacental tissue from 10 aneuploidies, and 2 unbalanced aberrations were evaluated. Balanced karyotype profiles were obtained from samples of healthy placentas and all samples from the same placenta appeared to have similar confidence intervals. CGH analysis of four cases of trisomy 21, three cases of trisomy 18, one case of trisomy 13, one case of trisomy 15 and one case of trisomy 7 all showed overrepresentation of the respective trisomic chromosome. The CGH profile was also in accordance with the karyotyping of a case with isochromosome 21. The CGH profile of a case with der (2)t(2;6)(q37.3;q22.2) revealed partial trisomy for chromosome 6 between q21 and q27. CGH may be a useful adjunct in prenatal genetic diagnosis when retrospective diagnosis is needed from archival samples.     

46,XY,18q+/46,XY,18q- mosaicism in a fragile X prenatal diagnosis

OBJECTIVES: We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q21) in which finally the 18q- cell line formed the embryo. This prenatal diagnosis was performed on a pregnant woman carrying a premutation in the FMR1 gene. The purpose of the current study was to characterise the final fetus genotype and to discuss how this chromosomal abnormality was originated. METHODS: Conventional cytogenetic analyses were performed from chorionic villi, amniocytes, and fetal blood samples in order to establish the fetal chromosome constitution. Molecular studies with microsatellite markers and CGH were carried out to this end. PCR and Southern blot were used to analyse the CGG-repeat region of the FMR1 gene. RESULTS: An initial chorionic villi sample analysis showed a normal allele for the fragile X syndrome, but an abnormal 46,XY,dup(18)(q21q23) karyotype. Amniocentesis was subsequently performed, and a different 46,XY,del(18)(q21) cell line was detected. Re-examination of original chorionic villi sample evidenced a mosaicism for 46,XY,dup(18)(q21q23)/46,XY,del(18)(q21). Molecular findings allowed us to determine that the deletion expands at least 20 Mb and that it is paternally inherited. CONCLUSION: Two different cell lines with structural abnormalities on chromosome 18 were formed as a consequence of an unequal sister chromatid exchange during the first post-zygotic division. This case reinforces the necessity of performing a karyotype in all prenatal diagnosis even when the indication is for a monogenic disease.     

A normal birth following preimplantation genetic diagnosis by FISH determination in the carriers of der(15)t(Y;15)(Yq12;15p11) translocations: two case reports

Purpose To investigate the clinical application of fluorescence in situ hybridization (FISH) for assessing chromosome disorders of embryos in preimplantation diagnosis of carriers with der(15)t(Y;15)(q12;p11) translocations. Methods Multicolor FISH was performed using directly-labelled DNA probes, chromosome X with one (DXZ1, Xp11.1-q11.1), but Y with two (DYZ3, Yp11.1-q11.1 and DYZ1, Yq12). Normal embryos were transferred on day 6 at blastocyst stage. Results Couple A: Three of 6 biopsied embryos were normal. Two normal blastocysts were transferred, but no pregnancy was achieved. Couple B: Three of 6 biopsied embryos were normal. Two normal blastocysts were transferred. A normal male infant weighing 3,230 g was born by cesarean section on the 39th week of gestation. All of the remaining nonreplaced embryos showed mosaic or der(15). Conclusion Embryos from carries of der(15)t(Y;15)(q12;p11) translocation showed a high frequency of chromosome abnormalities. PGD is a valuable screen tool for those couples to treat their infertility and break the transmission of der(15) chromosome for their offspring.     

Prenatal diagnosis of a fetus affected with Down syndrome and deletion 1p36 syndrome by fluorescence in situ hybridization and spectral karyotyping

OBJECTIVE: A fetus having partial trisomy of the distal part of chromosome 21q due to a de novo translocation is reported here. METHOD: A 29-year-old woman received amniocentesis at 18 weeks of gestation because of abnormal ultrasound findings including bilateral choroid plexus cysts, atrioventricular septal defects, rocker-bottom feet, and possible hydrocephalus. RESULTS: Cytogenetic analysis revealed 46,XY, add(1)(p36.3), in which an additional material of unknown origin was attached to one of the terminal short arms of chromosome 1. Parental blood studies showed normal karyotypes in both parents. Spectral karyotyping was then performed and the origin of the additional material locating at chromosome 1p was found to be from chromosome 21. Conventional fluorescence in situ hybridization analysis was also used and confirmed the spectral karyotyping findings by use of a chromosome 21 specific painting probe, a locus specific probe localized within bands 21q22.13-q22.2 and a 21q subtelomeric probe. A hidden Down syndrome caused by a de novo translocation in this fetus was therefore diagnosed and the karyotype was designated as 46,XY, der(1)t(1;21)(p36.3;q22.1).ish der(1)(WCP21+, LSI 21+, 1pTEL-, 21q TEL+) de novo. Clinical features of the 1p36 deletion syndrome are also reviewed and may contribute to some features of this fetus. Termination of pregnancy was performed at 20 weeks of gestation. CONCLUSION: To our knowledge, our case appears to be the first to have partial monosomy 1p and partial trisomy 21q caused by de novo translocation being diagnosed prenatally.     

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.     

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.     

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.     

Prenatal diagnosis of trisomy 18p and distal 21q22.3 deletion

OBJECTIVES: To present the perinatal findings and molecular cytogenetic analysis of concomitant trisomy 18p (18p11.2-->pter) and distal 21q22.3 deletion. CASE AND METHODS: A 29-year-old woman, gravida 2 para 1, underwent amniocentesis at 17 weeks' gestation because she was a carrier of a balanced reciprocal translocation, 46,XX,t(18;21)(p11.2;q22.3). Cytogenetic analysis of the cultured amniocytes revealed a karyotype of 46,XX,der(21)t(18;21)(p11.2;q22.3). The fetus had a derivative chromosome 21 with an extra short arm of chromosome 18 attached to the terminal region of the long arm of chromosome 21. Level II sonograms did not find prominent structural anomalies. The pregnancy was terminated subsequently. At autopsy, the proband displayed a mild phenotype of hypertelorism, a small mouth, micrognathia, a narrowly arched palate, low-set ears, and clinodactyly. The brain and other organs were unremarkable. Genetic marker analysis showed a distal deletion at 21q22.3 and a breakpoint between D21S53 (present) and D21S212 (absent), centromeric to the known holoprosencephaly (HPE) minimal critical region D21S113-21qter. CONCLUSION: Genetic marker analysis helps in delineating the region of deletion in prenatally detected unbalanced cryptic translocation. Fetuses with concomitant trisomy 18p and distal 21q22.3 deletion may manifest inapparent phenotypic abnormalities in utero. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

Hypoplastic external genitalia in association with X;autosome chromosome translocation.

STUDY OBJECTIVE: To learn the relationship between X;autosome chromosome translocation and hypoplastic external genitalia. BACKGROUND: An X;autosome translocation usually presents with phenotypic features similar to Turner syndrome. PARTICIPANTS: We present three female siblings and their mother with X;autosome translocation and hypoplastic external genitalia. METHODS: Case presentation. RESULTS: Three female siblings, ages 14, 16, and 18 years, presented for routine checkup. All had been seen in the past for short stature, learning disability, and other features similar to those seen in Turner syndrome. At time of presentation, all three had primary amenorrhea. On genital exam, each was found to have hypoplastic external genitalia with absent clitoris and labia minora. Pelvic ultrasound in all subjects showed normal but prepubertal uterus and ovaries. Two subjects have unbalanced translocations with karyotype 46,X,der(9)t(9;X)(q11.2;q22.3). This abnormal chromosome complement results in the loss of the short arm of the X chromosome and the gain of an extra copy of the long arm of chromosome 9. The third subject and her mother have balanced translocations with the karyotype 46,X,t(9;X)(q11.2;q22.3). X-inactivation studies showed skewed inactivation of the normal X chromosome in the balanced translocation carriers, while the two girls with the unbalanced karyotype had skewed inactivation of the translocation product. All subjects have growth hormone deficiency. The oldest sibling was able to menstruate regularly after estrogen/progesterone therapy. The other two patients are currently receiving growth hormone and are gaining height. CONCLUSION: X;autosome translocations may be associated with hypoplastic external genitalia but normal internal genitalia. Balanced carriers can be fertile. To our knowledge, the presence of hypoplastic external genitalia in association with X;autosome translocation has not been previously reported. This should be added to the possible causes of hypoplastic external genitalia.     

Prenatal diagnosis and molecular cytogenetic characterization of chromosome 22q11.2 deletion syndrome associated with congenital heart defects

ObjectiveTo report prenatal diagnosis of 22q11.2 deletion syndrome in a pregnancy with congenital heart defects in the fetus.Case reportA 26-year-old, primigravid woman was referred for counseling at 24 weeks of gestation because of abnormal ultrasound findings of fetal congenital heart defects. The Level II ultrasound revealed a singleton fetus with heart defects including overriding aorta, small pulmonary artery, and ventricular septal defect. Cordocentesis was performed. The DNA extracted from the cord blood was analyzed by multiplex ligation-dependent amplification (MLPA). The MLPA showed deletion in the DiGeorge syndrome (DGS) critical region of chromosome 22 low copy number repeat (LCR) 22-A∼C. Conventional cytogenetic analysis revealed a normal male karyotype. Repeated amniocentesis and cordocentesis were performed. Whole-genome array comparative genomic hybridization (aCGH) on cord blood was performed. aCGH detected a 3.07-Mb deletion at 22q11.21. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype 46,XY. Metaphase fluorescence in situ hybridization (FISH) analysis on cultured amniocytes confirmed an interstitial 22q11.2 deletion.ConclusionPrenatal ultrasound findings of congenital heart defects indicate that the fetuses are at increased risk for chromosome abnormalities. Studies for 22q11.2 deletion syndrome should be considered adjunct to conventional karyotyping. Although FISH has become a standard procedure for diagnosis of 22q11.2 deletion syndrome, MLPA can potentially diagnose a broader spectrum of abnormalities, and aCGH analysis has the advantage of refining the 22q11.2 deletion breakpoints and detecting uncharacterized chromosome rearrangements or genomic imbalances.