Demand For Prenatal Diagnosis Research Articles

Prenatal Diagnosis of Cystic Fibrosis and Hemophilia: Incidental Findings and Weak Points.

Because of the progression of genetics and genomics, the demand for prenatal diagnosis (PD) for inherited genetic diseases has increased. However, several incidental findings may emerge during PD, like misattributed paternity, the evidence of disease in a parent, and the possible misinterpretation of the results because of complex alleles or de novo mutations that have several implications. In a retrospective observational study on all the couples referred to our Medical School (1993–2018) for PD of genetic inherited diseases (n = 1502), we selected the cases of PD for cystic fibrosis (CF, n = 239) and hemophilia A and B (HA, HB, n = 47), revising all incidental findings previously mentioned. We found one case in which a technical error led to PD of carrier in two siblings that were born affected by CF, four cases of misattributed paternity, eight cases of asymptomatic parents revealed as affected by CF transmembrane regulator (CFTR)-related disorders, a case of a novel complex allele that could have caused the diagnosis of CF in a carrier fetus, and a case of a de novo mutation in a mother (already a carrier) that caused hemophilia in a child that PD had revealed as healthy. We present these conditions as clinical cases and discuss the technical, clinical, ethical, and legal aspects to be considered.

Prenatal diagnosis in Portugal.

On practical terms we can say that prenatal diagnosis (PND) only started in Portugal in 1984 after the Abortion Act was approved by Parliament. Since then the demand for PND has been increasing, but we realise that the coverage of high-risk pregnancies as well as screening for fetal abnormalities in the general population are below the desirable levels. Among the factors that contribute to this we can mention the bad planning in some services, the low standard of ultrasound scans in the low-risk pregnancies, the small number of public cytogenetics laboratories performing fetal karyotyping, the scarcity of genetic counsellors and last but not least the inadequate limit of 16 weeks for termination of pregnancies in case of fetal malformation.

Prenatal diagnosis of cystic fibrosis: an experience of 181 cases

The demand for prenatal diagnosis (PD) of cystic fibrosis (CF) is increasing. We performed pre-test multidisciplinary counselling for 192 couples at CF reproductive risk. In 11/192 (5.7%) cases PD was not performed mainly because counselling revealed a reproductive risk for atypical (mild) CF, while 181 PDs were performed in couples revealed at high risk for CF mainly because they already had a CF child (148/181, 81.8%) or had been identified through cascade screening (28/181, 15.5%). In 167/181 (92.3%) cases (including two dichorionic twin pregnancies), PD was performed on chorionic villi, and in 14 on amniocyte DNA. Only 1/181 PD was unsuccessful. In all other cases, single tandem repeat analysis excluded maternal contamination, and PD was made within 7 days of sampling. In total 116/180 (64.4%) PDs were made with dot-blot analysis; 40 (22.2%) required gene sequencing; in 4/180 cases we tested the gene for large rearrangements; in 23/180 (12.8%) cases linkage analysis was necessary because parental mutation(s) were unknown. Forty-two out of 180 (23.3%) PDs revealed an affected foetus. All couples but one interrupted pregnancy. The first twin PD revealed the absence (1 foetus) and the presence of one mutation (the other foetus); the second twin PD revealed one parental mutation (1 foetus) and both parental mutations (the other foetus); the couple planned selective interruption. PD for CF should be performed in reference laboratories equipped for gene scanning and linkage analysis, with a multidisciplinary staff able to offer counselling to couples during all phases of PD.

Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is the second anterior horn cell disease in infants in which the genetic defect has been defined. SMARD1 results from mutations in the gene encoding the immunoglobulin micro-binding protein 2 (IGHMBP2) on chromosome 11q13. Our aim was to review the clinical features of 29 infants affected with SMARD1 and report on 26 novel IGHMBP2 mutations. Intrauterine growth retardation, weak cry, and foot deformities were the earliest symptoms of SMARD1. Most patients presented at the age of 1 to 6 months with respiratory distress due to diaphragmatic paralysis and progressive muscle weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves are also affected. Because of the poor prognosis, there is a demand for prenatal diagnosis, and clear diagnostic criteria for infantile SMARD1 are needed. The diagnosis of SMARD1 should be considered in infants with non-5q spinal muscular atrophy, neuropathy, and muscle weakness and/or respiratory distress of unclear cause. Furthermore, consanguineous parents of a child with sudden infant death syndrome should be examined for IGHMBP2 mutations.

DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and/or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester. The identification of mutations in the genes encoding keratins K5 and K14 as the cause of EBS opens up the possibility of much earlier diagnosis of the disease. We report here four cases in which prenatal testing was performed. In three of the cases the genetic lesions were unknown at the start of the pregnancy, requiring the identification of the causative mutation prior to testing fetal DNA. In two of the four cases novel mutations were identified in K14 and in the two remaining families, a previously identified type of mutation was found. Fetal DNA, obtained by chorionic villus sampling or amniocentesis, was analysed for the identified mutations. Three of the DNA samples were found to be normal; a mutant K14 allele was identified in the fourth case and the pregnancy was terminated. These results demonstrate the feasibility of DNA-based prenatal testing for EBS in families where causative mutations can be found. Copyright © 2000 John Wiley & Sons, Ltd.

DIFFICULTIES AND DILEMMAS IN THE MANAGEMENT OF CONGENITAL ANOMALIES IN TWIN PREGNANCY

SUMMARYBoth the incidence of twin pregnancy and the demand for prenatal diagnosis are increasing. Unfortunately, biochemical screening and ultrasound scanning are less reliable for prenatal diagnosis in twin pregnancies than in singletons. Amniocentesis and chorionic villous biopsy are usually diagnostic in singleton pregnancies but may be marred by sampling errors in twin gestations. Where a congenital anomaly has been diagnosed in a twin pregnancy, difficult decisions may have to be made, especially if one twin is unaffected. In these cases, special skills are required to ensure that adequate information, psychological support and optimal medical care are provided.

MUTATION-BASED PRENATAL DIAGNOSIS OF HERLITZ JUNCTIONAL EPIDERMOLYSIS BULLOSA

Epidermolysis bullosa (EB) is a group of heritable diseases which manifest with blistering and erosions of the skin and mucous membranes. Due of life-threatening complications and significant long-term morbidity associated with the severe, neonatal lethal (Herlitz) form of junctional EB (H-JEB), there has been a demand for prenatal diagnosis from families at risk for recurrence. Previously, the only reliable method of prenatal diagnosis of EB was a fetal skin biopsy performed at 16-20 weeks' gestation and analysed by electron microscopy. Recently, the genes LAMA3, LAMB3, and LAMC2, encoding the polypeptide subunits of laminin 5, an anchoring filament protein, have been shown to contain mutations in H-JEB. In this study, direct detection of pathogenetic mutations in the laminin 5 genes was used to perform polymerase chain reaction (PCR)-based prenatal testing. DNA was obtained by chorionic villus sampling (CVS) at 10-15 weeks or amniocentesis at 12-19 weeks' gestation in 15 families at risk for recurrence of JEB. In 13 cases, the fetus was predicted to be either genetically normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in all cases by the birth of a healthy child. In two cases, an affected fetus was predicted, and the diagnosis was confirmed by subsequent fetal skin biopsy. These results demonstrate that DNA-based prenatal testing offers an early, expedient, and accurate method of prenatal diagnosis or an exclusion of Herlitz JEB.

Prenatal Diagnosis for Recessive Dystrophic Epidermolysis Bullosa in 10 Families by Mutation and Haplotype Analysis in the Type VII Collagen Gene (COL7A1)

Epidermolysis bullosa (EB) is a group of heritable diseases that manifest as blistering and erosions of the skin and mucous membranes. In the dystrophic forms of EB (DEB), the diagnostic hallmark is abnormalities in the anchoring fibrils, attachment structures beneath the cutaneous basement membrane zone. The major component of anchoring fibrils is type VII collagen, and DEB has been linked to the type VII collagen gene (COL7A1) at 3p21, with no evidence for locus heterogeneity. Due to life-threatening complications and significant long-term morbidity associated with the severe, mutilating form of recessive dystrophic EB (RDEB), there has been a demand for prenatal diagnosis from families with affected offspring.Intragenic polymorphisms in COL7A1 and flanking microsatellite markers on chromosome 3p21, as well as detection of pathogenetic mutations in families, were used to perform PCR-based prenatal diagnosis from DNA obtained by chorionic villus sampling at 10-15 weeks or amniocentesis at 12-15 weeks gestation in 10 families at risk for recurrence of RDEB.In nine cases, the fetus was predicted to be normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in nine cases by the birth of a healthy child. In one case, an affected fetus was predicted, and the diagnosis was confirmed by fetal skin biopsy.DNA-based prenatal diagnosis of RDEB offers an early, expedient method of testing which will largely replace the previously available invasive fetal skin biopsy at 18-20 weeks gestation.

Adult polycystic kidney disease: knowledge, experience, and attitudes to prenatal diagnosis.

One hundred and ninety subjects from 100 adult polycystic kidney disease (APKD) families on the North Western Regional Genetic Register were interviewed to determine the likely demand for prenatal diagnosis. A detailed questionnaire was used to assess understanding and experience of clinical, therapeutic, and genetic aspects of APKD. Major features of the disease (presence of renal cysts which can lead to renal failure) and forms of therapy (dialysis and transplantation) were known; knowledge of less common features was related to experience. The cohort had had genetic counselling and the majority knew the risk to their own offspring, although the mechanics of the mode of inheritance was often misunderstood. Uptake of presymptomatic ultrasound testing was high, and some implications of early diagnosis are noted. A minority changed their reproductive behaviour as a result of APKD, and although the majority felt a prenatal test should be available, only 23% at high risk of passing on the disease and contemplating children felt they would be interested, and so far only one request for prenatal diagnosis has been received. Thus, demand appears to be low and to be related to perception of the seriousness of APKD.

Experiences with prenatal diagnosis of sickle cell anemia and thalassemias in the first trimester of pregnancy: various aspects for the obstetrician

After an extensive educational campaign for the medical community in the area of the Westf. Wilhelms-University Münster five pregnancies at risk for sickle cell anemia and thalassemias were investigated during the first trimester of pregnancy. Following chorionic villi sampling in one case a sickle cell anemia and in two other cases a beta-thalassemia could be excluded. In two additional cases a homozygous beta-thalassemia was proven and in one of the cases the first trimester diagnosis was confirmed in the second trimester by fetal blood sampling. Because of the migration patterns in Europe there is currently a considerable demand for prenatal diagnosis of beta-thalassemias in West-Germany after proper information of the population at risk.