Wen-Lin Chen

Prenatal diagnosis of partial trisomy 3p(3p23-->pter) and monosomy 7q(7q36-->qter) in a fetus with microcephaly alobar holoprosencephaly and cyclopia.

We report the prenatal diagnosis of partial trisomy 3p(3p23→pter) and monosomy 7q(7q36→qter) in a fetus with microcephaly, alobar holoprosencephaly and cyclopia. A 26‐year‐old primigravida woman was referred for genetic counselling at 23 gestational weeks due to sonographic findings of intra‐uterine growth retardation and cranio‐facial abnormalities. Level II ultrasonograms further demonstrated alobar holoprosencephaly, a proboscis above the eye and a single median orbit consistent with cyclopia. Genetic analysis and fluorescence in situ hybridization on cells obtained from amniocentesis showed distal 3p trisomy (3p23→pter) and 7q36 deletion, 46,XX,der(7)t(3;7)(p23;q36), resulting from a paternal t(3;7) reciprocal translocation. The pregnancy was terminated. Autopsy further confirmed the presence of arrhinencephaly, agenesis of the corpus callosum and a single ventricle of the brain. The phenotype of this antenatally diagnosed case is compared with those observed in 10 previously reported cases with simultaneous occurrence of partial trisomy 3p and terminal deletion 7q. All cases are associated with severe forms of holoprosencephaly and facial dysmorphism. This delineates an autosomal imbalance syndrome or a dosage effect involving duplication of distal 3p/deficiency of terminal 7q and dysmorphogenesis of the forebrain and mid‐face. Copyright

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array comparative genomic hybridization characterization using uncultured amniocytes and literature review.

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot.

Trisomy 7 mosaicism at amniocentesis: Interphase FISH, QF-PCR, and aCGH analyses on uncultured amniocytes for rapid distinguishing of true mosaicism from pseudomosaicism

OBJECTIVE To present prenatal diagnosis of true trisomy 7 mosaicism. MATERIALS, METHODS AND RESULTS A 36-year-old woman underwent amniocentesis at 18 weeks of gestation. Amniocentesis revealed a karyotype of 47,XY,+7[20]/46,XY[9]. The parental karyotypes were normal. Repeated amniocentesis was performed at 20 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes manifested a genomic gain in chromosome 7. Quantitative fluorescent polymerase chain reaction (QF-PCR) analysis on uncultured amniocytes showed a biparental diallelic pattern with a dosage increase in the maternal allele. Interphase fluorescence in situ hybridization (FISH) on uncultured amniocytes revealed three 7q-specific signals in 13 of 50 (26%) of the cells. The cultured amniocytes had a karyotype of 47,XY,+7[12]/46,XY[14]. The ultrasound findings were unremarkable. The pregnancy was subsequently terminated, and a fetus was delivered with facial dysmorphisms. Postnatal tissue samplings revealed the mosaic trisomy 7 level of 37.5% (15/40), 30% (12/40), 42.5% (17/40), 82.5% (33/40), 52.5% (21/40), and 27.5% (11/40) in skin, liver, lungs, placenta, membrane, and cord, respectively. The cord blood had a karyotype of 46,XY. PEG1/MEST methylation-sensitive high-resolution melting PCR assay of cord blood showed no uniparental disomy for chromosome 7. CONCLUSION Interphase FISH, QF-PCR, and aCGH analyses on uncultured amniocytes are useful for rapid distinguishing of true mosaicism from pseudomosaicism for trisomy 7 at amniocentesis. Cord blood sampling for confirmation of fetal trisomy 7 mosaicism is not practical.

Mosaic deletion-duplication syndrome of chromosome 3: Prenatal molecular cytogenetic diagnosis using cultured and uncultured amniocytes and association with fetoplacental discrepancy

OBJECTIVE To present prenatal molecular cytogenetic diagnosis of mosaicism for terminal 3p deletion and distal 3q duplication using cultured and uncultured amniocytes, and the association with fetoplacental discrepancy. MATERIALS, METHODS, AND RESULTS A 35-year-old primigravid woman was referred for genetic counseling at 21 weeks of gestation because of 20% (5/25 colonies) mosaicism for add(3)(p26) detected by amniocentesis. Repeated amniocenteses were performed. Array comparative genomic hybridization (aCGH) and interphase fluorescence in situ hybridization (FISH) were applied in the uncultured amniocytes. aCGH analysis detected 0.15-Mb microdeletion of 3p26.3 with CHL1 haploinsufficiency and a 49.42-Mb duplication of 3q24-q29 in the uncultured amniocytes. Interphase FISH analysis revealed 27.3% mosaicism (12/44 cells) in the uncultured amniocytes. Metaphase FISH analysis revealed 23.3% mosaicism (7/30 cells) in the cultured amniocytes. Conventional cytogenetic analysis showed a karyotype of 46,XX,der(3)(qter → q24::p26.3 → qter)[10]/46,XX[20] (33% mosaicism). Subsequent fetal blood sampling showed a karyotype of 46,XX,der(3) (qter→q24::p26.3→qter)[5]/46,XX[35] (12.5% mosaicism). The parents elected to terminate the pregnancy, and a malformed fetus was delivered at 24 weeks of gestation with characteristic facial dysmorphism and clinodactyly of the hands. Cytogenetic analysis of the extraembryonic tissues revealed the results of 46,XX (40 cells) in placenta, 25% mosaicism (10/40 cells) in amniotic membrane and 50% mosaicism (20/40 cells) in umbilical cord. CONCLUSION Our presentation highlights the utility of molecular cytogenetic technologies in prenatal diagnosis of rare mosaic chromosome rearrangements and provides evidence for fetoplacental discrepancy under such circumstances.

Partial Trisomy 10q (10q25.1 →qter) and Partial Monosomy 13q (13q34→qter) Presenting With Fetal Pyelectasis: Prenatal Diagnosis and Array Comparative Genomic Hybridization Characterization

Distal trisomy 10q syndrome is a well-defined but rare syndrome characterized by a high and large forehead, a round and flat face, epicanthal folds, hypertelorism, fine eyebrows, antimongoloid slants, low-set ears, cleft palate, micrognathia, a flat nasal bridge, a short nose, a bow-shaped mouth, microcephaly, hypotonia, joint laxity, clinodactyly, scoliosis, a short neck, growth retardation, psychomotor disorders, and cardiac, ocular and renal abnormalities [1–6]. The critical region for distal trisomy 10q is proposed to be on 10q24 qter [5]. The phenotype in patients with 13q deletion syndrome has been divided into three groups. Group 1 comprises deletions not extending into q32 and is associated with milder features and less developmental delay. Group 2 comprises distal deletions including at least a part of q32 and is associated with one or more major malformations related to the brain, eye, distal extremities, and gastrointestinal and genitourinary systems. Group 3 comprises more distal deletions involving q33–q34, and is associated with mental retardation in the absence of major malformations and growth retardation [7]. A concomitant occurrence of distal trisomy 10q and distal 13q deletion is unusual. We report array comparative genomic hybridization (aCGH) characterization of partial trisomy 10q (10q25.1 qter) and partial monosomy 13q (13q34 qter) in a fetus associated with fetal pyelectasis. A 37-year-old woman, gravida 3, para 1, consulted the hospital at 20 gestational weeks for genetic counseling and confirmation of fetal aneuploidy. She previously had a healthy 3-year-old daughter and experienced one spontaneous abortion. During this pregnancy, she had undergone amniocentesis at 16 gestational weeks because of advanced maternal age. A derivative chromosome 13, or der(13), was found with a segment of distal 10q translocated to the terminal region of the long arm of chromosome 13. Level II ultrasound revealed a singleton with fetal biometry equivalent to 20 weeks and bilateral pyelectasis with the left pelvis measuring 0.61 × 0.80 cm and the right pelvis measuring 0.51 × 0.50 cm (Figure 1). At 21 gestational weeks, repeat amniocentesis revealed a der(13) in the fetus (Figure 2). The father was found to carry a balanced reciprocal translocation between distal 10q and distal 13q (Figure 3). The parents opted to terminate the pregnancy. A 324-g malformed male fetus was delivered with a high and large forehead, a flat face, hypertelorism, a flat nasal bridge, low-set ears, micrognathia, a short neck and clinodactyly (Figure 4). Bacterial artificial chromosome (BAC)-based aCGH of fetal DNA using CMDX BAC-based aCGH CA2500 chips (CMDX, Irvine, PARTIAL TRISOMY 10Q (10Q25.1 QTER) AND PARTIAL MONOSOMY 13Q (13Q34 QTER) PRESENTING WITH FETAL PYELECTASIS: PRENATAL DIAGNOSIS AND ARRAY COMPARATIVE GENOMIC HYBRIDIZATION CHARACTERIZATION

Prenatal diagnosis and molecular cytogenetic characterization of a de novo interstitial deletion of 7q (7q22.1→q31.1).

We present prenatal diagnosis and molecular cytogenetic characterization of de novo interstitial deletion of 7q (7q22.1→q31.1) by aCGH, FISH and QF-PCR in a fetus with an abnormal maternal serum screening result and ultrasound findings of facial cleft and hypogenitalism. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of ZKSCAN5, ARPC1A, CYP3A43, RELN, LAMB1, IMMP2L and DOCK4 in this case.

Prenatal diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin associated with fetal hypotonia, arthrogryposis, scoliosis and hyperextensible joints.

We present rapid aneuploidy diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin by aCGH using uncultured amniocytes in a fetus with hypotonia, scoliosis, arthrogryposis, hyperextensible joints, facial dysmorphism, ventricular septal defect, pulmonary stenosis, clenched hands, clubfoot, scalp edema and right hydronephrosis. We discuss the genotype-phenotype correlation of 3q duplication syndrome and terminal 14q deletion syndrome. We demonstrate that fetuses with a paternal-origin deletion of 14q involving the 14q32.2 imprinted region may prenatally present the upd(14)mat-like phenotype such as hypotonia, scoliosis, arthrogryposis and hyperextensible joints.

Discrepancy in the trisomy mosaicism level between cultured amniocytes and uncultured amniocytes in prenatally detected mosaic trisomy 20

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan Department of Medicine, Mackay Medical College, New Taipei City, Taiwan Department of Biotechnology, Asia University, Taichung, Taiwan e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan f Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Chang Gung University, Tao-Yuan, Taiwan Department of Obstetrics and Gynecology, School of Medicine, Taipei Medical University, Taipei, Taiwan Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan Department of Bioengineering, Tatung University, Taipei, Taiwan

Monozygotic twins with trisomy 18 of paternal origin: prenatal diagnosis and molecular cytogenetic characterization in a pregnancy with one structurally abnormal living fetus and one intrauterine fetal demise.

OBJECTIVE To present prenatal diagnosis and molecular cytogenetic characterization of trisomy 18 in a monozygotic twin pregnancy, with one structurally abnormal living fetus and one intrauterine fetal demise. CASE REPORT A 38-year-old woman was referred for amniocentesis at 16 weeks of gestation because of advanced maternal age. Prenatal ultrasound revealed a monozygotic twin pregnancy, with one structurally abnormal living fetus, and one fetal demise. The body structure details of the dead fetus could not be identified, whereas holoprosencephaly and omphalocele were identified in the living fetus on prenatal ultrasound. Quantitative fluorescent polymerase chain reaction assays using polymorphic DNA markers specific for chromosome 21 and chromosome 18, were applied to the uncultured amniocytes in the amniotic cavity of the living fetus and the cultured amniocytes in the amniotic cavity of the fetus with intrauterine fetal demise. The specimen showed a dosage ratio of 2:1 (paternal:maternal) for chromosome 18-specific markers in both twins. The result was consistent with monozygosity and trisomy 18, and the trisomy 18 was possibly caused by a paternal second meiotic division non-disjunction error or a postzygotic mitotic error. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+18 in both twins. The pregnancy was terminated at 19 weeks of gestation, and a 2g small-for-date macerated twin A and a 166g malformed twin B were delivered. Twin A manifested cebocephaly and omphalocele, and twin B manifested premaxillary agenesis and omphalocele. CONCLUSION The present case provides evidence that fetal wastage may occur in one of the co-twins in monozygotic twins associated with trisomy 18, and this may in part explain the very rare occurrence of living monozygotic twins with trisomy 18.

Prenatal diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 13

We present prenatal diagnosis and molecular cytogenetic characterization of de novo mosaic r(13). A 32-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Amniocentesis revealed a karyotype of 46,XY,r(13)[33]/45,XY,-13[19]. aCGH on uncultured amniocytes at repeated amniocentesis detected a 4.22-Mb deletion at 13q34. Interphase FISH on 100 uncultured amniocytes showed the ratio of r(13):-13:idic r(13) as 85%:13%:2%. The cord blood had a karyotype of 46,XY,r(13)[91]/46,XY,idic r(13)[6]/45,XY,-13[3]. The placenta had a karyotype of 46,XY,mar(13)[31]/45,XY,-13[3]. Metaphase FISH confirmed that the marker chromosomes in placenta were derived from chromosome 13. aCGH on cultured placental cells detected a 77.81-Mb deletion at 13q13.3-q34. The fetus postnatally manifested facial dysmorphism. Prenatal diagnosis of r(13) should alert mosaicism for deletion/duplication of r(13) and distal 13q deletion. Fetoplacental chromosomal discrepancy of r(13) may exist in case of mosaic r(13) detected by amniocentesis.