Prenatal diagnosis of monosomy 4p14→pter and trisomy 11q25→qter: clinical presentations and outcomes

We present the case of a pregnant woman with low free β-HCG in maternal serum Down syndrome screening that led to prenatal diagnosis of a fetus with 46,XY,der(4)t(4;11)(p14; q25). This chromosomal aneuploidy resulted from unbalanced segregation of a paternal balanced translocation, t(4;11)(p14;q25). Prenatal ultrasound revealed intrauterine growth restriction, cleft lip and palate, a thick nuchal fold, a single umbilical artery, and pyelectasis. Array-based comparative genomic hybridization and short tandem repeat markers further located the exact breakpoint of translocation. The woman had her pregnancy terminated at 23 weeks of gestational age. The proband had general appearance of Wolf–Hirschhorn syndrome and some unique findings, including single umbilical artery, severe immunoglobulin deficiency, scalp defect, and underlying bony defect. Our case underscores the importance of fetal karyotyping when low maternal serum free β-HCG is found. It also adds information on the fetal presentations of monosomy 4p14→pter and trisomy 11q25→qter. Copyright © 2005 John Wiley & Sons, Ltd.     

Deletion 15q24-26 in prenatally detected diaphragmatic hernia: increasing evidence of a candidate region for diaphragmatic development

Survival of children with congenital diaphragmatic hernia (CDH) is mainly dependent on the extent of lung hypoplasia and the presence of additional congenital anomalies or chromosomal aberrations. A chromosomal deletion 15q25-q26.2 in a fetus with prenatally diagnosed CDH and growth retardation is reported. Despite optimal pre- and neonatal management the baby died shortly after birth. There is increasing evidence that the long arm of chromosome 15, and especially the region 15q24 to 15q26, plays a crucial role in the development of the diaphragm. The finding of a deletion within 15q24-26 in a fetus with CDH has to be considered a predictor of poor prognosis. It is of utmost interest for proper parental counselling to search in fetuses with CDH for subtle chromosomal lesions paying special attention to chromosome 15q. Copyright © 2001 John Wiley & Sons, Ltd.     

Denaturing high-performance liquid chromatography (DHPLC)-based prenatal diagnosis for tuberous sclerosis

Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition (affecting 1 in 6000 individuals) caused by various mutations in either the hamartin (TSC1) or the tuberin gene (TSC2). This allelic and non-allelic heterogeneity makes genetic counseling and prenatal diagnosis difficult, especially as a significant proportion of TSC cases are due to de novo mutations. For this reason the identification of the disease causing mutation is mandatory for accurate counseling, yet current mutation detection methods such as single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) are labor intensive with limited detection efficiency. Denaturing high-performance liquid chromatography (DHPLC) is a high-throughput, semi-automated mutation detection system with a reported mutation detection rate close to 100% for PCR fragments of up to 800 bp. We used a recently described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC. The fetus was found not to have inherited the deleterious mutation and the DHPLC diagnosis was confirmed by haplotype analysis. This represents the first DHPLC-based prenatal diagnosis of a genetic disease. Copyright © 2001 John Wiley & Sons, Ltd.     

The importance of investigating for uniparental disomy in prenatally identified balanced acrocentric rearrangements

We report the finding of paternal isodisomy for chromosome 14 in a fetus found to have a der(14;14)(q10;q10) by amniocentesis. The pregnancy was complicated by severe polyhydramnios and elevated amniotic fluid alpha-fetoprotein (AFP). The infant showed features consistent with paternal uniparental disomy (UPD) including postnatal growth retardation, poor respiratory function, feeding difficulties, and evidence of hypertrophic cardiomyopathy. The present case, in addition to other reported cases of UPD involving balanced acrocentric rearrangements, supports testing for UPD in prenatally detected Robertsonian translocations and isochromosomes. Copyright © 2002 John Wiley & Sons, Ltd.     

Confined placental mosaicism for trisomy 14 and maternal uniparental disomy in association with elevated second trimester maternal serum human chorionic gonadotrophin and third trimester fetal growth restriction

A case of confined placental mosaicism (CPM) and maternal uniparental isodisomy 14 identified after placental karyotype revealed trisomy 14 in a newborn with intrauterine growth restriction (IUGR) and minor dysmorphic features is reported. During the second trimester of the pregnancy, multiple marker screening revealed an increased risk for Down syndrome of >1 in 10. The maternal serum human chorionic gonadotrophin (MShCG) was markedly elevated at 4.19 MoM. Amniocentesis revealed a normal 46,XX karyotype. Fetal growth restriction has been associated with elevated MShCG and placental aneuploidy with CPM for chromosomes 2, 7, 9 and 16. The present case of CPM for chromosome 14 was also associated with fetal growth restriction and elevated second trimester MShCG, suggesting a common link. Further studies need to be done to determine if indeed elevation of second trimester MShCG is associated with increased risk of CPM. The present case again demonstrates the need to perform placental karyotype in unexplained fetal growth restriction. Copyright © 2001 John Wiley & Sons, Ltd.     

Unexpected structural chromosome rearrangements in prenatal diagnosis

Among 5315 prenatal diagnoses performed for various indications (maternal age, neural tube defect, metabolic diseases, X-linked diseases, pathologic pregnancies) 29 unexpected structural chromosome rearrangements were found in fetal cells. Fourteen were de novo chromosome rearrangements, six unbalanced, and eight balanced. Fifteen were inherited and balanced rearrangements. This high frequency of structural anomalies is discussed.     

Rare cell isolation using antibodies covalently linked to slides: application to fetal cells in maternal blood

We describe here a new type of method for isolation of rare cell populations in biological fluids. The method is based on the anthraquinone technology for covalent binding of molecules to a polymer surface. An anthraquinone molecule conjugated via a linker to an electrophilic group (AQ Immobilizer™ reagent, Exiqon A/S) is covalently bound to a polymer surface by UV irradiation. The electrophilic group of this AQ reagent can covalently bind a specific antibody directed against a specific cell marker. Applying a cell sample to the functional surface, the cells having the specific cell marker on the cell surface will bind to the antibody on the functional surface. Using this technique, even extremely small cell populations may be isolated. We succeeded in isolating fetal cells from maternal blood samples in the first trimester for chromosome defects genetic diagnosis. Copyright © 2003 John Wiley & Sons, Ltd.