DNA-based prenatal carrier detection for group a xeroderma pigmentosum in a chorionic villus sample

DNA-based prenatal carrier detection of group A xeroderma pigmentosum (XP-A) is reported. Chorionic villus sampling was done at the tenth gestational week in a pregnant woman whose first child suffers from XP-A. Genomic DNAs from the villi, proband, and parents were PCR (polymerase chain reaction)-amplified using three sets of primers, because the PCR and a subsequent enzyme digestion with HphI, AlwNI, or MseI may detect the three most frequent mutations of the XP-A complementing gene (XPAC) in Japanese XP-A patients. The results showed that the proband is a homozygote and that the parents and fetus are heterozygotes for a base substitution at the 3′ acceptor site of intron 3 of XPAC, indicating that the fetus is a healthy carrier of XP-A. This is the first case of prenatal carrier detection of the disorder.     

Resorbed co-twin as an explanation for discrepant chorionic villus results: Non-mosaic 47,XX, +16 in villi (direct and culture) with normal (46,XX) amniotic fluid and neonatal blood

Non-mosaic trisomy 16 was observed in chorionic villus cytotrophoblasts (direct) as well as cultured mesenchymal core cells derived from the pregnancy of a 38-year-old woman. Chromosome preparations from amniotic fluid and neonatal cultures (cord blood) were 46,XX. Normal fetal growth as determined by serial ultrasound examinations occurred throughout the pregnancy, which resulted in a healthy 2724 g female. Multiple biopsies taken from the umbilical cord, placental cotyledons, and fetal membranes were 46,XX. However, a placental nodule and three of six cultures initiated from membranes (amnion and chorion) showed 46,XX/47,XX, + 16 mosaicism. We propose that the trisomy 16 cells arose from residual villi derived from a trisomic cotwin that never developed. This case further demonstrates that normal fetal growth may presage normal outcome irrespective of cytogenetic findings in cytotrophoblasts (direct) and cultured mesenchymal core cells.     

Changes in maternal serum alpha-fetoprotein levels associated with intrauterine genetic diagnostic procedures

The amount of fetal—maternal transfusion during invasive intrauterine diagnostic instrumentation was determined by measuring the increase in maternal serum alpha-fetoprotein (Δ AFP) caused by the procedure. Fetal liver biopsy or fetoscopy for purposes other than blood sampling caused a mean Δ AFP of 11.4 ng/ml and 34.2 ng/ml, respectively. Fetoscopy with fetal blood sampling produced a mean Δ AFP of 211.8 ng/ml, while fetoscopy followed by placentesis caused a mean Δ AFP of 462.8 ng/ml (representing a 1.07 ml fetal—maternal transfusion). Although this magnitude of fetal—maternal transfusion is an acceptable risk for the fetus, it is a sufficient transfusion to cause blood cell antigen sensitization.     

Evaluation of maternal serum dimeric inhibin a as a first-trimester marker of down's syndrome

While second-trimester prenatal screening programmes for Down's syndrome have become established in prenatal care, it would be advantageous to be able to offer screening in earlier preganancy. To this end, we have evaluated a new potential maternal serum marker, dimeric inhibin A, as a possible first-trimester marker. Dimeric inhibin A was measured in propsectively collected maternal serum from 23 cases of Down's syndrome and matched chromosomally normal controls, at 11–13 weeks' gestation. Levels of this protein were significantly elevated in the Down's pregnancies compared with the control pregnancies. The median multiple of the normal median (MOM) for the Down's samples was 2.46 (95 per cent confidence interval: 2.11–3.26, P<0.0001 vs. controls). These results suggest that dimeric inhibin A is a useful discriminator of Down's-affected pregnancies from normal pregnancies in the first trimester and that sensitive screening in combination with maternal age and other possible markers may be practicable in the first trimester.     

Infantile hypophosphatasia: Successful prenatal assessment by testing for tissue-non-specific alkaline phosphatase isoenzyme gene mutations

We successfully assessed a fetus at risk for lethal infantile hypophosphatasia using amniocyte DNA and allele-specific oligonucleotide (ASO) probes for two missense mutations in the tissue-non-specific alkaline phosphatase isoenzyme (TNSALP) gene. The nucleotide changes had been discovered in a sister who died at 8 months of age from this inborn error of metabolism. The mother was known to carry the 747 (cDNA) G→A transition, whereas her husband and 5-year-old daughter, who were also healthy, carried the 1309 A→T transversion. Amniocytes, obtained at 16 weeks' gestation, provided genomic DNA for polymerase chain reaction (PCR) amplification of the appropriate TNSALP gene exons. ASO hybridization revealed absence of the 747A mutation and presence of the 1309T base change in the fetus, indicating a carrier for hypophosphatasia. At 8 months of age, the offspring was in excellent health and without any radiological evidence of skeletal disease. His serum ALP activity and plasma pyridoxal 5′-phosphate level were decreased and increased, respectively, at levels consistent with the prenatal assessment. The ASO studies were confirmed postnatally using peripheral blood leukocyte DNA. This is the first application of direct mutational analysis to assess a fetus at risk for hypophosphatasia.     

Prenatal diagnosis of sanfilippo disease type C using a simple fluorometric enzyme assay

A new fluorogenic substrate, 4-methylumbelliferyl β-D-glucosaminide, was used for the assay of acetyl CoA:glucosaminide N-acetyltransferase in chorionic villi, cultured villus cells, and amniocytes. Optimal conditions for the assay and the ranges of enzyme activity were established for the various types of fetal cells. This simple fluorometric assay provides a reliable method for early prenatal diagnosis of Sanfilippo disease type C which is more convenient than current methods using radiolabelled substrates. The method was applied to amniotic fluid cells and fetal fibroblasts from an at-risk pregnancy in which an affected fetus was diagnosed by two-dimensional electrophoresis of glycosaminoglycans in the amniotic fluid.     

Autosomal recessive polycystic kidney disease. Problems of prenatal diagnosis

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by different proportions of cystic dilated collecting ducts invariably associated with congenital hepatic fibrosis. Because of the nearly regular arrangement of nephrons and collecting ducts, disturbances have been postulated to act rather late on embryological grounds. Prenatal diagnoses seem to confirm this observation, as can be demonstrated in our cases and those reported in the literature. Increased echogenicity and renal enlargement are the main ultrasonographic signs of ARPKD; oligohydramnios is characteristic but not always present. Repeated sono-graphic measurements of the kidney length seem to be the most useful parameter. As differential diagnoses, autosomal dominant polycystic kidney disease as well as Meckel syndrome have to be taken into consideration. The prognosis of cases with oligohydramnios is usually poor. In genetic counselling, the possibility of prenatal diagnosis in the second trimester of pregnancy should be given with caution.     

Second trimester prenatal diagnosis of the Jarcho-Levin syndrome

The Jarche–Levin syndrome (spondylothoracic dysostosis) is a rare autosomal recessive disorder characterized by a short neck, short trunk and a constricted thorax due to multiple rib and vertebral defects; other visceral malformations are occasionally present. Most cases die in infancy due to respiratory failure. In this report we describe two cases in one family from the United Kingdom. Prenatal diagnosis by ultrasound examination during the second trimester was successfully accomplished in the second case.     

Revised estimates and projections of down syndrome births in the United States,and the effects of prenatal diagnosis utilization, 1970–2002

The objectives of this study were to: (1) calculate revised estimates and projections of United States annual Down syndrome (DS) births for 1970–2002, and (2) estimate the effects of amniocentesis on these baseline DS birth projections. Three models of amniocentesis utilization among 30–34 and ≧ 35-year-old women were considered. The recently revised Census Bureau birth projections, and new single year maternal age DS risk rates estimated from a 1970–1983 Ohio data set, were used. Data from all three Census Bureau projection series were analysed; series II was considered in depth since it is consistent with recent fertility levels. Assuming no use of amniocentesis, total estimated DS births dropped from about 4770 in 1970 to 4120 in 1980 (a 14 per cent decline), but are projected to a plateau of about 5100 by the year 1990 (a 24 per cent increase). DS births to women ≧ 35 would increase dramatically from about 1050 in 1980 to 1900 in 2000 (an 81 per cent increase). Assuming 1983 Ohio prenatal diagnosis ratios for women aged 30–34 (1.7 per cent) and ≧ 35 (23.4 per cent) are used nationally, an annual reduction of about 7 per cent of DS births in 1986 and 9 per cent in 2002 would result. Fifty and 70 per cent utilization among women 30–34 and 235, respectively, would reduce DS births by about 33 per cent in 1986 and 38 per cent in 2002. Therefore, if the projected increase in DS births is to be averted, utilization of prenatal diagnosis by ≧ 30-year-old women must increase substantially.     

Prenatal diagnosis of inherited metabolic disorders by quantitation of characteristic metabolites in amniotic fluid: Facts and future

An attempt is made to summarize as completely as possible what is known about the prenatal diagnosis of amino– and organic acidurias by direct measurement of characteristic metabolites in amniotic fluid, and to indicate which disorders can potentially be diagnosed prenatally by direct quantitation of metabolites. Furthermore, the disorders are mentioned in which the prenatal diagnosis was proven to be unsuccessful by this approach. The prenatal diagnoses of a case of propionic acidemia and a case of tyrosinemia type I in the 11th and 12th week of gestational age, respectively, are reported and the prospects of performing amniocentesis in the first trimester for prenatal diagnosis are discussed.