Meng Shan Lee

Unbalanced reciprocal translocations at amniocentesis

OBJECTIVEnTo present perinatal findings, modes of ascertainments, and modes of segregation in unbalanced reciprocal translocations detected at amniocentesis.nnnMATERIALS AND METHODSnBetween January 1987 and July 2010, 40 cases with unbalanced reciprocal translocations were diagnosed by amniocentesis at Mackay Memorial Hospital, Taipei, Taiwan. The 40 cases originated from 29 families; 21 families with one case, 7 families with two cases, and 1 family with five cases.nnnRESULTSnOf 40 cases, 33 (82.5%) presented fetal ultrasound abnormalities and 7 (17.5%) presented no ultrasound abnormalities. Of 40 cases, 36 (90%) had a segregation mode of adjacent-1 2:2 segregation, 3 (7.5%) had a segregation mode of 3:1 segregation with tertiary trisomy, and 1 (2.5%) had a segregation mode of 3:1 segregation with tertiary monosomy. Of 29 families, 7 (24.1%) had de novo translocations and 22 (75.9%) had inherited translocations. In seven de novo cases, the main modes of ascertainments included abnormal ultrasound findings (n = 5) and advanced maternal age (n = 2). In 22 inherited families, the main modes of first ascertainment included abnormal ultrasound findings (n = 8), a previous aneuploid child (n = 8), advanced maternal age (n = 4), parental carrier status (n = 1), and abnormal maternal serum screening results (n = 1). Among 22 inherited families, 9 (40.9%) had a known parental carrier status, but 13 (59.1%) were unaware of parental carrier status at amniocentesis.nnnCONCLUSIONnUnbalanced reciprocal translocations detected at amniocentesis are frequently associated with abnormal ultrasound findings. Prenatal diagnosis of an unbalanced translocation may incidentally detect a balanced translocation in the family. Prenatal diagnosis of fetal structural abnormalities should alert structural chromosome rearrangements and prompt cytogenetic analysis of the fetus and parents if necessary.

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

OBJECTIVEnTo present molecular cytogenetic characterization of prenatally detected inverted duplication and deletion of 9p, or inv dup del(9p).nnnMATERIALS, METHODS, AND RESULTSnA 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.nnnCONCLUSIONnFluorescence 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.

Abnormally Flat Facial Profile on Two- and Three-dimensional Ultrasound and Array Comparative Genomic Hybridization for the Diagnosis of Pallister-Killian Syndrome

124 A 40-year-old, gravida 2, para 1, woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Her husband was 43 years of age. Both parents were healthy, and there was no family history of congenital malformations. Amniocentesis revealed mosaicism for a supernumerary isochromosome consisting of two entire short arms of chromosome 12 or i(12)(p10). The karyotype was 47,XX,+i(12p)[16]/ 46,XX[9] derived from 25 colonies of amniocytes, with 64% (16/25) of the amniocytes being +i(12p). The parental karyotypes were normal. Prenatal ultrasound at 19+4 weeks of gestation revealed a normal volume of amniotic fluid, macrocephaly with a biparietal diameter of 5.01 cm (21.72 weeks), hypertelorism, an abdominal circumference of 15.27 cm (20.48 weeks), a femur length of 3 cm (19.26 weeks), and a flat face with a very small nose and protruding lips (Figures 1 and 2). A diagnosis of Pallister-Killian syndrome (PKS) was made. The pregnancy was subsequently terminated, and a 399-g fetus, with macrocephaly, a large coarse face, a long philtrum, retrognathia, a Cupid’s bow mouth with thin lips, a flattened nose with a low nasal bridge, anteverted nostrils, upslanting palpebral fissures and low-set ears, was delivered (Figures 3 and 4). Postnatal ABNORMALLY FLAT FACIAL PROFILE ON TWOAND THREE-DIMENSIONAL ULTRASOUND AND ARRAY COMPARATIVE GENOMIC HYBRIDIZATION FOR THE DIAGNOSIS OF PALLISTER-KILLIAN SYNDROME

Rapid aneuploidy diagnosis of partial trisomy 7q (7q34→qter) and partial monosomy 10q (10q26.12→qter) by array comparative genomic hybridization using uncultured amniocytes

OBJECTIVEnTo present rapid aneuploidy diagnosis (RAD) of partial trisomy 7q (7q34→qter) and partial monosomy 10q (10q26.12→qter) by array comparative genomic hybridization (aCGH) using uncultured amniocytes.nnnCASE REPORTnA 34-year-old, gravida 2, para 1, woman underwent amniocentesis at 20 weeks of gestation because of a previous mentally retarded child with an unbalanced reciprocal translocation inherited from the carrier father who had a karyotype of 46,XY,t(7;10) (q34;q26.12). Her first child was initially found to have a normal karyotype by routine cytogenetic analysis, but a cryptic chromosomal abnormality was subsequently diagnosed by aCGH. During this pregnancy, RAD by oligonucleotide-based aCGH using uncultured amniocytes revealed a 16.4-Mb duplication of 7q34-q36.3 and a 12.7-Mb deletion of 10q26.12-q26.3. Conventional cytogenetic analysis using cultured amniocytes revealed a karyotype of 46,XX,der(10)t(7;10)(q34;q26.12)pat. The parents elected to terminate the pregnancy. A malformed female fetus was delivered with a high prominent forehead, hypertelorism, epicanthic folds, a broad depressed nasal bridge, a prominent nose with anteverted nostrils, micrognathia, a short neck, large low-set ears, clinodactyly, small big toes, and normal female external genitalia.nnnCONCLUSIONnaCGH is a useful tool for RAD of subtle chromosomal rearrangements in pregnancy, especially under the circumstance of a previous abnormal child with an unbalanced translocation derived from a parental subtle reciprocal translocation.

Prenatal diagnosis of concomitant Wolf-Hirschhorn syndrome and split hand foot malformation associated with partial monosomy 4p (4p16.1->pter) and partial trisomy 10q (10q25.1->qter)

Chih-Ping Chen1,2,3,4*, Yann-Jang Chen5,6, Schu-Rern Chern2, Fuu-Jen Tsai7, Tung-Yao Chang1, Chen-Chi Lee1, Dai-Dyi Town1, Meng-Shan Lee1 and Wayseen Wang2 1Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan 2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan 3Department of Biotechnology, Asia University, Taichung, Taiwan 4School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan 5Faculty of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan 6Department of Pediatrics, Veteran General Hospital, Taipei, Taiwan 7Departments of Medical Genetics, and Medical Research, China Medical University Hospital, Taichung, Taiwan

Unbalanced and Balanced Acrocentric Rearrangements Involving Chromosomes Other Than Chromosome 21 at Amniocentesis

OBJECTIVEnTo investigate unbalanced and balanced acrocentric rearrangements involving chromosomes other than chromosome 21 at amniocentesis.nnnMATERIALS AND METHODSnFrom January 1987 to September 2009, 31,194 amniocenteses were performed at Mackay Memorial Hospital, Taipei, Taiwan. Two cases with unbalanced acrocentric rearrangements involving chromosomes other than chromosome 21 from two families, and 24 cases with balanced acrocentric rearrangements involving chromosomes other than chromosome 21 from 21 families were diagnosed and investigated.nnnRESULTSnWe detected i(13q13q), +13 (one case), rob(13q14q), +13 (one case), rob(13q14q) (16 cases), rob(14q15q) (five cases), rob(13q15q) (one case), rob(15q22q) (one case), and mosaic rob(14q22q) (one case). Of the 25 cases that underwent parental cytogenetic investigation, six arose de novo and 19 were inherited (10 maternal and nine paternal). The 16 families with an inherited Robertsonian translocation included rob(13q14q) (11 families), rob(14q15q) (four families), and rob(15q22q) (one family). Of these 16 families, only two had known parental carrier status prior to the first amniocentesis, while the other 14 were aware of a parental carrier status only after prenatal diagnosis of a fetus with a heterologous Robertsonian translocation. The 18 fetuses with balanced heterologous Robertsonian translocations inherited them from six maternal carriers of rob(13q14q), four paternal carriers of rob(13q14q), four paternal carriers of rob(14q15q), and one maternal carrier of rob(15q22q). Neither UPD14 nor UPD15 was detected in any of the 16 cases tested for UPD.nnnCONCLUSIONnConcerning acrocentric rearrangements involving chromosomes other than chromosome 21, we found a frequency of 0.0064% for unbalanced rearrangements and 0.0769% for balanced rearrangements at amniocentesis in this study. rob(13q14q) was the most common and rob(14q15q) the second most common rearrangement. Of the families with an inherited translocation, 87.5% were aware of parental carrier status only after prenatal diagnosis of a fetus with a translocation by amniocentesis.

A 12 Mb deletion of 6p24.1 -> pter in an 18-gestational-week fetus with orofacial clefting, the Dandy-Walker malformation and bilateral multicystic kidneys

We report an 18-gestational-week fetus with oligohydramnios, orofacial clefting, bilateral multicystic kidneys and the Dandy-Walker malformation. Characteristic craniofacial features include a turricephalic prominent forehead, hypertelorism, low-set ears, a flat nasal bridge, mid-face hypoplasia, bilateral cleft lip and palate, and a thick nuchal fold. Array-comparative genomic hybridization (CGH) analysis demonstrated a 12Mb deletion of 6p24.1-->pter.

Unbalanced and Balanced Heterologous Acrocentric Rearrangements Involving Chromosome 21 at Amniocentesis

OBJECTIVEnTo present unbalanced and balanced heterologous acrocentric rearrangements involving chromosome 21 at amniocentesis.nnnMATERIALS AND METHODSnBetween January 1987 and September 2009, 31,194 amniocenteses were performed at Mackay Memorial Hospital, Taipei, Taiwan. Two cases with an unbalanced heterologous acrocentric rearrangements involving chromosome 21 from two families and seven cases with balanced heterologous acrocentric rearrangements involving chromosome 21 from five families were diagnosed and investigated.nnnRESULTSnWe detected rob(14q21q),+21 (one case), rob(13q21q),+21 (one case), rob(14q21q) (four cases), rob(13q21q) (one case) and rob(15q21q) (two cases). Of the nine cases that underwent parental cytogenetic investigation, one was de novo and eight were inherited (five maternal and three paternal). The six families with an inherited acrocentric rearrangement included rob(14q21q) (three families), rob(13q21q) (two families) and rob(15q21q) (one family). Of these six families, three had a known parental carrier status before the first amniocentesis, while the other three were aware of their parental carrier status only after prenatal diagnosis of a fetus with a heterologous acrocentric rearrangement. The seven fetuses with a balanced heterologous acrocentric rearrangement were inherited from two paternal carriers of rob(14q21q), one maternal carrier of rob(14q21q), one maternal carrier of rob(13q21q), and one maternal carrier of rob(15q21q). No uniparental disomy 14 was detected in any of the three cases with rob(14q21q) tested for uniparental disomy.nnnCONCLUSIONnConcerning heterologous acrocentric rearrangements involving chromosome 21, the frequency of unbalanced rearrangements was 0.0064% and that of balanced rearrangements was 0.0224% at amniocentesis. In this study, rob(14q21q) was the most common, and rob(13q21q) and rob(15q21q) were the second most common rearrangements. Of the six families with an inherited heterologous acrocentric rearrangement involving chromosome 21, 50% (3/6) were aware of their parental carrier status only after prenatal diagnosis of a fetus with a translocation by amniocentesis.