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.     

Prenatal findings in trisomy 16q of paternal origin.

A 34-year-old pregnant woman was referred at 30 weeks of gestation with suspected fetal congenital heart disease. On prenatal ultrasound the following anomalies were detected: intra-uterine growth retardation, micrognathia, coarctation of the aorta with ventricular and atrial septal defects, ambiguous external genitalia, and clinodactyly of one hand with adducted thumb. Prenatal karyotyping was offered but refused by the patient. The fetus was delivered by Caesarean section due to fetal distress at 36 weeks of gestation. The neonate, weighing 2150 g was transferred to the neonatal intensive care unit, where he died 10 days later. The karyotype from peripheral blood lymphocytes was 46,XY+der(20)t(16;20)(q12.1;p13)pat. The maternal karyotype was unremarkable, whereas the father had the translocation t(16;20)(q12.1;p13). Necropsy confirmed all the prenatal findings. These are discussed together with the implications of the chromosomal diagnosis and the pertinent literature is reviewed.     

Partial monosomy 13q (13q21.32--->qter) and partial trisomy 8p (8p1--->pter) presenting with anencephaly and increased nuchal translucency: array comparative genomic hybridization characterization

ObjectiveTo present array comparative genomic hybridization (aCGH) characterization of partial monosomy 13q (13q21.32→qter) and partial trisomy 8p (8p12→pter) presenting with anencephaly and increased nuchal translucency (NT).Case ReportA 34-year-old primigravid woman was referred to the hospital at 12 weeks of gestation for termination of the pregnancy because of major structural abnormalities of the fetus. Prenatal ultrasound revealed a malformed fetus with anencephaly and an increased NT thickness of 5 mm at 12 weeks of gestation. Cytogenetic analysis of the fetus revealed a derivative chromosome 13. The mother was subsequently found to carry a balanced reciprocal translocation between 8p12 and 13q21. Bacterial artificial chromosome-based aCGH using fetal DNA demonstrated partial trisomy 8p and partial monosomy 13q [arr cgh 8p23.3p12 (RP11-1150M5→RP11-1145H12)×3, 13q21.32q34 (RP11-326B4→RP11-450H16)×1]. Oligonucleotide-based aCGH showed a 36.7-Mb duplication of distal 8p and a 48.4-Mb deletion of distal 13q. The fetal karyotype was 46,XY,der(13) t(8;13)(p12;q21.32)mat. The maternal karyotype was 46,XX,t(8;13)(p12;q21.32).ConclusionThe 13q deletion syndrome can be associated with neural tube defects and increased NT in the first trimester. Prenatal sonographic detection of neural tube defects should alert chromosomal abnormalities and prompt cytogenetic investigation, which may lead to the identification of an unexpected parental translocation involving chromosomal segments associated with neural tube development.     

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.     

Uniparental disomy in fetuses diagnosed with balanced Robertsonian translocations: risk estimate

Forty-two fetuses with non-homologous Robertsonian translocations were analyzed for uniparental disomy (UPD). One fetus with a de novo translocation t(13q;14q) had maternal isodisomy of chromosome 14. In a summary of the published data (including the present study), 315 cases were analyzed for UPD after prenatal diagnosis of balanced Robertsonian translocations, of these two fetuses had UPD, giving a risk estimate of 0.65% (CI 0.2-2.3). This risk justifies the recommendation of UPD analysis in fetuses diagnosed prenatally with Robertsonian translocations, with the emphasis on the chromosomes known to contain imprinted genes, such as 14 and 15. We also discuss the possibility of UPD in offspring of Robertsonian translocation carriers with normal karyotype. Based on the risk for UPD in fetuses with Robertsonian translocation we suggest to test these fetuses for UPD and to do so on amniocytes rather than chorionic villi when the risk for unbalanced karyotype is approximately 1%, comparable to the risk for UPD.     

Prenatal findings and molecular cytogenetic analyses of partial trisomy 12q (12q24.32-->qter) and partial monosomy 21q (21q22.2-->qter)

OBJECTIVES: To present the prenatal findings and molecular cytogenetic analyses of partial trisomy 12q and partial monosomy 21q, and a review of the literature. METHODS: Amniocentesis was performed at 23 gestational weeks in a 33-year-old woman because of abnormal sonographic findings. Amniocentesis revealed a derivative chromosome 21, or der(21), with a deletion on the region of 21q22.2 and an addendum of a small chromosomal segment of unknown origin. The maternal karyotype was subsequently found to be 46,XX,t(12;21)(q24.32;q22.2). Level II ultrasound showed microcephaly, micrognathia, a ventricular septal defect, and rocker-bottom feet. The pregnancy was terminated. A malformed infant was delivered without the phenotype of holoprosencephaly (HPE). Fluorescence in situ hybridization (FISH) and polymorphic DNA markers were used to investigate the involved chromosomal segments. RESULTS: FISH study showed the absence of the signal of 21q subtelomeric probe and the presence of the signal of 12q subtelomeric probe in the der(21).The fetal karyotype was 46,XY,der(21) t(12;21)(q24.32;q22.2)mat. Genetic marker analysis showed a deletion at 21q22.2 and a breakpoint between D21S156 (present) and D21S1245 (absent). The deleted segment was measured about 4.5 Mb encompassing the HPE critical region. CONCLUSIONS: Molecular genetic analyses help in determining the prenatally detected unbalanced cryptic translocation as well as parental balanced subtle translocation. A duplication of 12q24.32-->qter and a deletion of 21q22.2-->qter may be associated with prenatal sonographic findings of microcephaly, borderline ventriculomegaly and cerebellar hypoplasia, micrognathia, a ventricular septal defect, and rocker-bottom feet. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15

We report the prenatal diagnosis of a fetus with a de novo Robertsonian translocation: 45,XY,der(15;15)(q10;q10). Although Robertsonian translocations are common chromosomal rearrangements, those involving homologous chromosomes are infrequent. Since chromosome 15 is imprinted, uniparental disomy (UPD) is a concern when chromosomal rearrangements involving chromosome 15 are identified. In the present case, UPD studies showed normal biparental inheritance. In contrast to the fact that most homologous acrocentric rearrangements are isochromosomes, these results indicate postzygotic formation of a Robertsonian translocation between biparentally inherited chromosomes 15.     

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.     

Prenatal search for UPD 14 and UPD 15 in 83 cases of familial and de novo heterologous Robertsonian translocations

OBJECTIVES: The presence in the conceptus of a Robertsonian translocation predisposes to UPD formation, mainly by post-zygotic events of chromosome abnormality rescue. This is due to the increased risk of generating aneuploid zygotes because the rearranged chromosome and the respective homologues are prone to non-disjunction errors. Given this, carriers and karyotypically normal individuals conceived from a parent with a Robertsonian translocation are at risk for UPD. Abnormal phenotypes due to an imprinting effect have been found to be associated with UPD 14 and 15.The aim of the study was to refine, at the time of prenatal diagnosis, the risk for UPD 14 and 15 in a population with Robertsonian translocations involving these chromosomes. METHODS: Sixty-five cases of familial and de novo heterologous Robertsonian translocations involving chromosomes 14 and 15 and 18 fetuses with a normal karyotype, but conceived by a Robertsonian translocation carrier were prenatally studied to investigate the presence of UPD for chromosomes 14 and 15. RESULTS: Of the 65 Robertsonian translocation carriers, one fetus with a de novo der(14;21) showed maternal UPD 14. None of the 18 fetuses with a normal karyotype had UPD. CONCLUSION: Our data, combined with other previous prenatal investigations provide a general risk estimate for UPD 14 and 15 of 0.6%. Nevertheless, combining our data and those previously reported, all three fetuses with UPD had a de novo Robertsonian translocation, thus suggesting a risk of UPD formation of about 3% for this specific group of translocation carriers.     

Prenatal diagnosis of de novo (7;19)(q11.2;q13.3) translocation associated with a thick corpus callosum and Wilms tumor of the kidneys

We present a case of prenatal diagnosis of a de novo (7;19)(q11.2;q13.3) translocation associated with ultrasound features, including enlarged cisterna magna, normal vermis, thick corpus callosum, micrognathia, small and low-set ears and right hyperechogenic kidney. Karyotyping was performed at 24 weeks of gestation. Termination of pregnancy was accepted at the parents' request. Postmortem examination confirmed the prenatal findings, but revealed bilateral Wilms tumors of the kidneys. Parental karyotype was normal.     

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.     

Characterization of a balanced complex chromosomal rearrangement carrier ascertained through a fetus with dup15q26.3 and del5p15.33: case report

Abstract

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes which rarely appear in individuals with normal phenotypes. These individuals report fertility problems, recurrent miscarriages, or congenital anomalies in newborn offspring as a consequence of either meiotic failure or imbalanced chromosome segregation. A CCR involving chromosomes 5, 15, and 18 was discovered in a phenotypically normal man through a fetus with congenital malformations and partial trisomy of chromosome 15 and monosomy of chromosome 5. Ultrasound examination at 20 weeks of gestation showed severe oligoamnios and hydrothorax. Prenatal cytogenetic analysis and array comparative genomic hybridization (array-CGH) revealed a female fetus with dup15q26.3 and del5p15.33. We diagnosed the CCR using three-color fluorescence in situ hybridization (three-color FISH), and a balanced CCR using array-CGH and FISH was diagnosed in the paternal karyotype. The father is a carrier of a balanced translocation 46,XY,t(5;15;18)(p15.31;q26.3;p11.2). Due to the complexity of these rearrangements the diagnosis is difficult and the reproductive outcome uncertain. Reporting such rare cases is important to enable such information to be used for genetic counseling in similar situations and help estimate the risk of miscarriage or of newborns with congenital abnormalities.     

Molecular characterisation of a prenatally diagnosed 5q15q21.3 deletion and review of the literature

BACKGROUND: Ultrasound examination performed on a 32-year old woman at 30 weeks' gestation showed the presence of fetal malformations. Amniocentesis was performed. METHODS AND RESULTS: Cytogenetic analysis of cultured amniocytes revealed an interstitial deletion of the long arm of chromosome 5. Molecular studies confirmed that the deletion included the 5q15-21.3 region and was 14 Mb in size. Therefore, the karyotype was: 46,XY,del(5)(q15q21.3). In addition, analysis of polymorphic DNA markers showed that the deletion was of paternal origin. CONCLUSIONS: The pregnancy was terminated at 34 weeks' gestation. At autopsy, the fetus displayed dysmorphic features, thin limbs and renal abnormalities. The clinical findings observed in the fetus as well as in 20 cases reported previously allowed us to further delineate the phenotype of such interstitial 5q15q21.3 deletions.     

Detection of mosaic 15q11.1-q11.2 deletion encompassing NBEAP1 and POTEB in a fetus with diffuse lymphangiomatosis

Objective

We present cytogenetic and molecular cytogenetic diagnoses of mosaic deletion of chromosome 15q11.1-q11.2 in a fetus with diffuse lymphangiomatosis.

Molecular cytogenetic characterization of 1q42.3q44 deletion and 8q24.3 duplication in a fetus with single umbilical artery and ventricular septal defects

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of a chromosome 1q42.3q44 deletion and 8q24.3 duplication in a fetus with single umbilical artery and ventricular septal defects, and we discuss the genotype–phenotype correlation.Case reportHere, we describe a fetus with abnormal sonography findings showing a single umbilical artery and ventricular septal defects. Conventional karyotyping initially described the fetus as 46,XX,1q? and molecular cytogenetic analysis (CMA) revealed a 13-Mb deletion and 4.6-Mb duplication of regions 1q42.3q44 and 8q24.3, respectively. The father's karyotype was 46,XY. The mother's karyotype was 46,XX,t(1;8)(q42;q24). Therefore, the karyotype of the fetus was identified as 46,XX,der(1)t(1;8)(q42;q24) mat. After genetic counseling, the couple chose to terminate the pregnancy. We suggest that the ACTN2, RYR2 and PUF60 genes may be responsible for the ultrasound abnormalities observed in the fetus.ConclusionTo the best of our knowledge, this is the first report of a 1q deletion and 8q duplication identified by prenatal detection. The application of karyotype analysis and CMA provides more accurate characterization for unidentified chromosomal anomalies, and benefits appropriate genetic counseling in the clinic.     

Prenatal diagnosis of a 9q34.3 microdeletion by array-CGH in a fetus with an apparently balanced translocation

OBJECTIVES: Use high-resolution genome analysis to clarify the genomic integrity in a fetus with a cytogenetically balanced translocation t(2;9)(q11.2;q34.3). METHODS: High resolution molecular cytogenetic analyses including G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and array-comparative genomic hybridization (CGH) were performed on cultured cells, and DNA extracted from chorionic villus sample (CVS), amniotic fluid cells and fetal tissue. In addition, a custom fosmid-based tiling path 9q34.3 microarray with a resolution of 35-40 kb was used for array-CGH. RESULTS: GTG-banding analysis showed an apparently balanced de novo translocation between the long arms of chromosomes 2 and 9; t(2;9)(q11.2;q34.3). Array-CGH using a targeted chromosomal microarray analysis (CMA) uncovered a submicroscopic deletion of the subtelomeric region of 9q34.3 revealing the unbalanced nature of the rearrangement. These results were confirmed independently by FISH. The deletion was delimited to 2.7 Mb in size using the 9q34.3 fosmid-based tiling path array-CGH. CONCLUSION: Array-CGH is a powerful tool for rapid detection of genomic imbalances associated with microdeletion/duplication syndromes and for the evaluation of de novo apparently balanced translocation to enable high-resolution genomic analysis at the breakpoints. Prenatal diagnosis of chromosomal rearrangements involving dosage-sensitive genomic regions is an important adjuvant to prenatal care and provides more accurate information for counseling and informed decision making.     

Prenatal diagnosis of de novo t(2;18;14)(q33.1;q12.2;q31.2), dup(5)(q34q34), del(7)(p21.1p21.1), and del(10)(q25.3q25.3) and a review of the prenatally ascertained de novo apparently balanced complex and multiple chromosomal rearrangements

OBJECTIVES: To present the prenatal diagnosis of a de novo complex chromosomal rearrangement (CCR) associated with de novo interstitial deletions and duplication and to review the literature. CASE AND METHODS: Amniocentesis was performed at 18 weeks' gestation because of an increased risk for Down syndrome based on maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening. Amniocentesis revealed a karyotype of 46,XY,t(2;18;14)(q33.1;q12.2;q31.2),dup(5)(q34q34),del(7)(p21.1p21.1), del(10)(q25.3q25.3). The parental karyotypes were normal. The pregnancy was terminated. The fetus manifested facial dysmorphism, clinodactyly of both hands, and hypoplasia of the left great toe. Spectral karyotyping (SKY), cytogenetic polymorphism, and polymorphic DNA markers were used to investigate the imbalances and the origin of the de novo aberrant chromosomes. RESULTS: SKY showed a three-way CCR. Cytogenetic polymorphism investigation of the derivative chromosome 14 of the fetus and the parental chromosomes 14 determined the maternal origin of the translocation. Polymorphic DNA marker analysis confirmed the maternal origin of the de novo interstitial deletions and duplication. No cryptic imbalance at or near the breakpoints of the CCR was detected by the molecular analysis. CONCLUSIONS: De novo apparently balanced CCRs may be associated with imbalances in other chromosomes. We suggest further investigation and re-evaluation of cryptic or subtle imbalances in all cases classified as de novo apparently balanced CCRs.     

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.     

Segregation of digital number with partial monosomy or trisomy of 13q in familial 5;13 translocation.

It has been postulated that the deletion of band 13q22 may be associated with digital malformations, especially thumb and big toe anomalies. We report a family where the mother is carrying a balanced translocation between chromosomes 5p15 and 13q22. The offspring have a specific and well-defined phenotype depending on which is the unbalanced chromosome in the karyotype. When a partial trisomy of 13q22-->qter is present, the fetuses have polydactyly in the four limbs, and when the fetus is carrying a partial monosomy of this portion, an oligodactyly in all members can be observed.     

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

OBJECTIVE: To explore the utility of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of microphthalmia and linear skin defects syndrome. METHODS: We used karyotype analysis, FISH and array CGH to investigate an X;Y translocation. Replication studies were done on cultured amniocytes and lymphoblasts. RESULTS: We describe a severe case of MLS syndrome that presented prenatally with multiple anomalies including cystic hygroma, microphthalmia, intrauterine growth restriction and a complex congenital heart defect. Cytogenetic analysis of amniocytes revealed an unbalanced de novo translocation between chromosomes X and Y [karyotype 46,X,der(X)t(X;Y)(p22.3;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2 (Tuple1 x 2)]. MLS diagnosis was made at birth and the prenatal karyotype was confirmed. Replication studies showed the derivative X chromosome was the inactive X. Array CGH confirmed the X and Y imbalances seen in the karyotype and also showed twelve BACs in the MLS region were deleted as a result of the translocation. FISH with BAC clones verified the array findings and placed the X breakpoint in Xp22.2, resulting in the amended karyotype, 46,X,der(X)t(X;Y)(p22.2;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2(Tuple1 x 2) arr cgh Xp22.33p22.2(LLNOYCO3M15D10 -->GS1-590J6)x 1,Yq11.222q23(RP11-20H21-->RP11-79J10)x 1. CONCLUSION: The sensitivity of array CGH was valuable in detecting monosomy of the MLS critical region. Array CGH should be considered for the prenatal diagnosis of this syndrome.