Strategies for prenatal and preimplantation genetic diagnosis in Marfan syndrome (MFS)

Marfan syndrome (MFS) is an autosomal dominant disorder with a prevalence of 2–3 per 10 000 individuals. Symptoms range from skeletal overgrowth, cutaneous striae to ectopia lentis and aortic dilatation leading to dissection. Prenatal diagnosis was until recently mainly performed in familial cases by linkage analysis. However, mutation detection has become available with thorough screening methods. The phenotypic variability observed in MFS makes reproductive options difficult, as molecular diagnosis cannot predict clinical severity of the disease. Data are presented on 15 prenatal and/or preimplantation genetic diagnoses (PGD) in nine families, originating from Belgium, the Netherlands, Spain and France. In four families data from linkage analysis were used, whereas in five other families the causative FBN1 mutation was characterised. Four PGD cycles in two couples led to one ongoing pregnancy. In addition, two amniocenteses and nine chorionic villus (CV) samplings were performed. In five pregnancies an affected fetus was diagnosed. In one of them, the couple chose to continue the pregnancy and an affected child was born, whereas the other four couples decided to terminate the pregnancy. It is expected that the greater availability of mutation testing of the FBN1 gene will increase requests for prenatal diagnosis. PGD appears to be an acceptable alternative for couples facing ethical reproductive dilemmas. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of trisomy 9. Six cases and a review of the literature

Six prenatally diagnosed cases of trisomy 9 are reported and 22 previously reported cases are reviewed; the difficulty of genetic counselling for such cases and the variation in the percentage of trisomic cells in different tissues, thus making accurate diagnosis of trisomy 9 difficult, are emphasized. In addition to karyotyping results, ultrasound findings are important in achieving diagnoses. Finally, a course of action when prenatal trisomy 9 is detected is proposed.     

Preimplantation genetic diagnosis for aneuploidy screening in early human embryos: a review

Embryonic aneuploidies may be responsible for pregnancy failure in many IVF patients. In recent years, fluorescent in situ hybridisation (FISH) for multiple chromosomes has been used to document a high frequency of chromosomal errors and aneuploidy in human preimplantation embryos and, after embryo biopsy, to select embryos that are more likely to implant. Such studies suggest that women with recurrent miscarriage and advanced maternal age may benefit most from preimplantation genetic diagnosis with aneuploidy screening (PGD-AS). The success of PGD-AS is likely to be enhanced by new technologies, such as comparative genomic hybridisation, which enable full karyotyping of single cells. Copyright © 2002 John Wiley & Sons, Ltd.     

Trisomy 13 mosaicism: study of serial cytogenetic changes in a case from early pregnancy to infancy

We report a patient whose chorionic villus sampling showed a nonmosaic trisomy 13 [46,XX,der(13;13)(q10;q10)]. Subsequent amniocentesis and cordocentesis showed varying percentages of abnormal cells (77 and 78% in two amniocentesis; 14% in cordocentesis) and mosaic trisomy 13 was impressed. Prenatal fetal ultrasound scanning revealed only mild structural abnormalities (echogenic cardiac foci, transient lemon head, transient skin oedema). The mother chose to continue the pregnancy. Karyotyping of the cord blood, peripheral blood, umbilical cord, urine, and chorion were performed postpartum. The process of correction appeared to exist in the placenta (indirect evidence from coexistence of trisomy 13 [46,XX,der(13;13)(q10,q10)], euploidy [46,XX], aneuploidy [46,XX,–13, +mar], and monosomy 13 [45,XX,–13] in the chorion at birth). The baby had survived beyond eight months of age at the time of submission. Few structural abnormalities except low-set ears, absence of the 12th rib, and cardiomegaly with ventricular septal defect, were noted postnatally. The growth reached 95th percentile at the age of one month. Development milestones were not delayed at serial evaluations. Her ventricular septal defect was corrected surgically at the age of six months. Karyotypes of her skin fibroblasts, blood lymphocytes, and cardiac tissue were all normal [46,XX] at the time of surgery. Difficulties of the genetic counseling are also discussed. Copyright © 2004 John Wiley & Sons, Ltd.     

Novel mutations in the human CYP21 gene

The great majority of genetic defects underlying steroid 21-hydroxylase deficiency appear to result from intergenic recombinations between the homologous CYP21 and CYP21P genes. For a minority, novel sporadic point mutations have been detected. De novo mutations in CYP21 have also been reported, but only a few studies have systematically screened their occurrence. We here describe a population-based patient sample in order to estimate the rate of single-family (i.e. sporadic) and de novo germline mutations in the human CYP21 locus. Among 76 Finnish families were observed three single-family mutations and two de novo mutations in CYP21. The rates obtained, ∼5% and ∼2% for novel and de novo mutations, respectively, indicate that they are not rare and that their occurrence should not be ignored in genetic diagnostics of this disorder. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal molecular diagnosis in hypertrophic cardiomyopathy: report of the first case

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease that may cause premature sudden death, especially in teenagers and young adults. The recent progress in the molecular genetics of the disease has made genetic testing sometimes available in clinical practice. We report the case of a couple who still requested prenatal molecular testing after detailed information had been given through a multidisciplinary consultation. Prenatal diagnosis in HCM is associated with complex medical and psychological implications, in addition to general ethical considerations, as the potential value of the diagnosis is counterbalanced by the highly variable expression of the disease and the difficulty in predicting its evolution. The R403L mutation in the MYH7 gene had been previously identified in this family, characterized by a malignant form of HCM. In the specific context of this case, we decided to agree to the request of the parents and performed the prenatal diagnosis. To the best of our knowledge, this is the first report of a prenatal molecular diagnosis performed in the context of HCM. Copyright © 2004 John Wiley & Sons, Ltd.     

Fetal renal anomalies and genetic syndromes

Renal abnormalities are some of the commonest and most easily detectable anomalies on ultrasound. Many are an isolated finding but the prognosis may be altered considerably by the detection of other anomalies which could indicate a genetic disorder or syndrome. It is often easier to detect presupposed anomalies and the purpose of this article is to introduce and discuss those syndromes that may present with a renal abnormality on ultrasound. Common renal findings are presented with the range of additional anomalies that should be sought and suggested diagnostic tests. It should be remembered that although for many genetic conditions specific mutation analysis is now available, this usually requires pre‒pregnancy investigations. Furthermore, in some cases the definitive diagnosis may not be suspected until post mortem. By this time it may be too late to establish a cell line to confirm the suspicion using laboratory methods. It is therefore important to take tissue samples antenatally where possible, or at delivery, as postnatal samples may have a high culture failure rate. Copyright © 2001 John Wiley & Sons, Ltd.