Prenatal diagnosis of sex chromosomal inversion, translocation and deletion.

The aim of the present study was to perform comprehensive prenatal diagnosis using various detection techniques on a fetus in a high­risk pregnant woman, and to provide genetic counseling for the patient and her family so as to avoid birth defects. The routine karyotype analysis via amniocentesis, fluorescence in situ hybridization, and whole genome microarray technique were performed for the prenatal diagnosis of the fetus. The fetal karyotype was 46,X,ish der(X) inv(X)(p22.3q28)t(X;Y)(q28;q11.2)(XYqter+,SRY­,DXZ1+, RP11­64L19+,STS+,XYpter+); namely, one fetal X chromosome belonged to the derivative imbalanced chromosome and this chromosome demonstrated complex chromosomal rearrangements involving inversion, translocation and deletion. Notably, pericentric inversion between Xp22.3 and Xq28 was identified, and the chromosomal microarray technique confirmed that the long arm q28 of the derivative X chromosome had a 1.241­Mb deletion in Xq28, which included Online Mendelian Inheritance in Man genes such as coagulation factor VIII, glucose­6­phosphate dehydrogenase, inhibitor of nuclear factor­κB kinase subunit γ, trimethyllysine hydroxylase ε, Ras­related protein Rab­39B and chloride intracellular channel 2. In addition, this chromosome also exhibited the local translocation of fragment Yq11.21­q11.23, which did not include the sex determining region Y gene. This fetus demonstrated deletion, inversion and translocation syndrome, and may exhibit the corresponding clinical phenotypes (e.g., intellectual disability or general delayed development) (1) of such chromosome abnormalities after birth. Therefore, in prenatal diagnosis, a variety of genetic diagnostic techniques should be comprehensively used based on specific clinical situations, which may accurately reveal the nature, sources and manifestations of the derivative chromosome abnormalities and avoid the birth of children with defects.

[Prenatal diagnosis of a case with 46,XX,del(4),dup(21)].

OBJECTIVE: To investigate the genetic cause and prognosis of a fetus with a rare karyotype. METHODS: Fluorescence in situ hybridization (FISH) was used for verifying a structural chromosomal abnormality detected by conventional karyotyping analysis. Whole genome DNA microarray was used to analyze copy number variations carried by the fetus. RESULTS: The fetus was found to have a 46,XX,dup(21)(?q21q22) karyotype, which was verified by FISH analysis as repetition of chromosome 21 region, namely nuc ish 21q22×3. Whole genome DNA microarray confirmed that there was a 17.87 Mb duplication in the 21q21.3q22.3 region, which involved GATA1, JAK2 and ALL genes and spanned the Down syndrome region. The genes are implicated in craniofacial abnormalities, cardiac abnormalities, mental retardation, growth retardation, limb abnormalities. In addition, there was also an 8.43 Mb deletion in the 4p16.1p16.3 region, which involved FGFR3, LETM1, WHSC1 and WHSC2 and other 64 OMIM genes and spanned the Wolf-Hirschhorn syndrome region. The genes are implicated in growth retardation, craniofacial abnormalities, cardiac abnormalities, mental retardation, and hypotonia. After consultation, the family chose to terminate the pregnancy at 25th week of gestation. CONCLUSION: FISH can help to verify structural chromosome abnormalities suspected by conventional karyotyping analysis. Combined with whole genome microarray, these can determine copy number variation and its region containing the disease genes, and facilitate clinical analysis of the fetus.

[Detection of a fetus with paternally derived 2q37.3 microdeletion and 20p13p12.2 microduplication using whole genome microarray technology].

OBJECTIVE: To perform prenatal diagnosis for a fetus with multiple malformations. METHODS: The fetus was subjected to routine karyotyping and whole genome microarray analysis. The parents were subjected to high-resolution chromosome analysis. RESULTS: Fetal ultrasound at 28+4 weeks has indicated intrauterine growth restriction, left kidney agenesis, right kidney dysplasia, ventricular septal defect, and polyhydramnios. Chromosomal analysis showed that the fetus has a karyotype of 46,XY,der(2),der(20), t(2;20)(q37.3;p12.2), t(5;15) (q12.2;q25) pat. SNP array analysis confirmed that the fetus has a 5.283 Mb deletion at 2q37.3 and a 11.641 Mb duplication at 20p13p12.2. High-resolution chromosome analysis suggested that the father has a karyotype of 46,XY,t(2;20)(q37.3;p12.2),t(5;15)(q12.2;q25), while the mother has a normal karyotype. CONCLUSION: The abnormal phenotype of the fetus may be attributed to a 2q37.3 microdeletion and a 20p13p12.2 microduplication. The father has carried a complex translocation involving four chromosomes. To increase the chance for successful pregnancy, genetic diagnosis and/or assisted reproductive technology are warranted.

[Genetic and prenatal diagnosis of a pregnant women with mental retardation].

OBJECTIVE: To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies. METHODS: G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus. RESULTS: The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week. CONCLUSION: Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype.

[Analysis of relationship between patients with chromosomal translocation and the outcome of pregnancy].

OBJECTIVE: To explore the relationship between chromosome translocation and their phenotypic effect by analyzing the patients with loss pregnancy and avoiding fetuses with chromosomal abnormalities. METHODS: A total of 3067 cases with infertility or loss pregnancy were recruited to receive chromosome examination during January 2005 to December 2011 at Center of Prenatal Diagnosis, Peking University People's Hospital. Retrospective study was used to analyze the chromosome karyotypes and infertility or loss pregnancy. RESULTS: In 72 cases of patients with chromosome translocation, there were 17 pregnancies with homology translocation in fetus. And the numbers of patients with loss pregnancy and sex apparatus malformations were 40 and 15 respectively. CONCLUSION: Chromosome translocation plays an important role in patients with loss pregnancy or infertility. And chromosome examination should be performed to exclude the possibility of chromosome abnormities in patients with obstinate infertility.

[Chromosome abnormalities and congenital heart diseases: a retrospective on 49 cases].

OBJECTIVE: To investigate the association between congenital heart diseases and chromosome abnormalities. METHODS: Patients with congenital heart diseases who underwent chromosome examinations during Jan 2006 and Dec. 2009 in the Center of Prenatal Diagnosis of Beijing University People's Hospital were recruited in the study. The association between chromosome karyotypes and types of congenital heart diseases was analyzed. RESULTS: Among the 49 patients with congenital heart diseases, trisomy 21 was established in 11 cases, trisomy 18 in 6 cases, trisomy 13 in 6 cases, trisomy 14 in 1 cases, trisomy 16 in 3 cases, trisomy 8 in 1 cases, trisomy 22 in 1 cases, sex chromosomal abnormalities in 8 cases, triploid in 2 cases, partial chromosomal trisomy in 8 cases, and 46,XX/XY, 5p-- in 2 cases. CONCLUSION: Chromosome abnormalities are associated with congenital heart diseases. Different abnormal chromosome karyotypes contribute to different types of congenital heart diseases. Prenatal chromosome examinations could be undertaken to detect congenital heart diseases.