Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case-by-case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell-free DNA.     

Artificial placenta and womb technology: Past,current, and future challenges towards clinical translation

Extreme prematurity remains a major cause of neonatal mortality and severe long-term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb-like environment, is the foundational principle of artificial placenta (AP) and womb (AW) technology. The concept has been studied during the past 60 years with limited success. However, recent technological advancements and a greater emphasis on mimicking utero-placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here, we review the rationale for and history of AP and AW technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research.     

The obstetrician's view: ethical and societal implications of non-invasive prenatal diagnosis

We believe non-invasive prenatal diagnosis is about to have a massive impact on the way fetal medicine is practised. There will be many great advantages and improvements, but the technology also has the potential to be used for non-medical reasons such as sex selection and paternity testing. We discuss some of the issues that may face obstetricians in the future as a result of this emerging technology. Copyright © 2006 John Wiley & Sons, Ltd.     

Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management

Cases where initial prenatal diagnosis was made of isolated unilateral multicystic kidney (UMCK) were reviewed to determine appropriate counselling and management strategies. For the 73 cases, chromosome abnormalities, pregnancy complications and family histories were reviewed. In addition, subsequently diagnosed birth defects, and pediatric medical and surgical outcomes were available for 54 cases. Of those with outcome information available renal/genital–urinary tract abnormalities were diagnosed subsequently in 33% and non-renal abnormalities in 16% of cases. Of the non-renal abnormalities, congenital heart defects were most frequent (7%). One chromosome abnormality, a trisomy 21, was present among 32 cases where karyotypes were known (3%). Amniotic fluid volume abnormalities were present in 11 cases but not predictive of associated anomalies, with the exception of one case where polyhydramnios accompanied multiple malformations consistent with VATER association. A family history of structural renal anomalies was reported in 11 cases (20%). There were 14 cases of partial or complete involution (25%), including two cases of complete prenatal involution of the cystic kidneys. No long-term associated morbidity such as hypertension or malignancy was present in our cohort. Based on our study and corroborating literature, amniocentesis should be offered to women when a seemingly isolated UMCK is detected on routine prenatal ultrasound. Furthermore, a detailed ultrasound with careful assessment of the fetal heart and contralateral kidney is indicated at diagnosis and during the third trimester to assess for further evidence of structural abnormalities, as well as amniotic fluid volume abnormalities. Careful assessment of the newborn is indicated with appropriate speciality referral as required. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of partial trisomy 12q: clinical presentations and outcome

We present a pregnant woman with a fetus prenatally diagnosed as 46, XY,der(4) t(4;12) (q35.1; q21.2). This defect resulted from the unbalanced segregation of a paternal balanced translocation, t(4;12) (q35.1; q21.2). Prenatal ultrasound revealed borderline ventriculomegaly, a thick nuchal fold, pericardial effusion, arthrogryposis, a single umbilical artery, and micropenis. Fluorescence in situ hybridization (FISH) with whole chromosome painting probe and microarray-based comparative genomic hybridization analysis further confirmed chromosomal gain of terminal 12q. The woman had her pregnancy terminated at 20 weeks of gestational age. When compared with previously reported cases, the proband had characteristics common to the phenotypes of partial trisomy 12q, including an abnormal facial appearance and multiple anomalies. Additionally, this case had previously unreported phenotypes, such as arthrogryposis, a single umbilical artery, and a micropenis. Regarding the outcome of partial trisomy 12q, the fetuses carrying trisomies distal to 12q24 have a good chance of extended postnatal survival. In contrast, the cases with trisomies involving a larger amount of 12q likely die prenatally or within a few days after birth. Copyright © 2005 John Wiley & Sons, Ltd.     

Psychological aspects of prenatal diagnosis and its implications in multiple pregnancies

Couples expecting twins are often unrealistically optimistic and are therefore unprepared for the complications as well as the practical and emotional impact the birth of twins can have on the family. All such couples will need information and support throughout the pregnancy and beyond. In this review, the various aspects that should be addressed are discussed, in particular, health care workers and counsellors need to be aware of the stress experienced by parents who have been through prolonged treatment for infertility or who face the special problems associated with the loss of one twin (implies the loss could be other than death). Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatal diagnosis and intrafamilial clinical heterogeneity of Fraser syndrome

Fraser syndrome (MIM 219000) is a rare disorder of autosomal recessive inheritance, characterized by the association of cryptophthalmos, syndactyly and genital abnormalities. Here we report on two cases of Fraser syndrome (cryptophthalmos syndrome) in a non-consanguineous couple, with variable expression in echographic, clinical and autopsy findings. Furthermore, we highlight the difficulties in prenatal diagnosis of Fraser syndrome. Copyright © 2002 John Wiley & Sons, Ltd.     

The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: challenges and progress made

Recently, we have witnessed the rapid translation into clinical practice of non-invasive prenatal testing for the common aneuploidies, most notably within the United States and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium-risk pregnancies identified by serum screening and/or ultrasound scanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single-gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour-intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single-gene disorders, and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here, we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders. © 2013 John Wiley & Sons, Ltd.     

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood. Copyright © 2002 John Wiley & Sons, Ltd.