Search

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2006.12.013 Byline: Wolfgang Holzgreve (1), Sinuhe Hahn (1), Xiao Yan Zhong (1), Olav Lapaire (1), Irene Hosli (1)(2), Sevgi Tercanli (1), Peter Miny (2), Claude Diesch (1) Author Affiliation: (1) Department of Obstetrics and Gynecology, University of Basel, Basel, Switzerland (2) Division of Medical Genetics, University of Basel, Basel, Switzerland Article History: Received 6 December 2006; Accepted 12 December 2006 Article Note: (footnote) Cite this article as: Holzgreve W, Miny P, Zhong XY, et al. Genetic communication between fetus and mother: short- and long-term consequences. Am J Obstet Gynecol 2007;196;xx-xx

OBJECTIVE: We wanted to test whether the recently described method of using the transferrin receptor system for fluorescence-activated cell-sorter enrichment of nucleated red blood cells can be used for prenatal diagnosis from maternal blood. STUDY DESIGN: Instead of the laborious, expensive fluorescence-activated cell-sorter system, we used the newly described magnetic-activated cell sorter. RESULTS: An effective enrichment could be achieved with separation of lymphocyte subsets. With the transferrin receptor, however, the enrichment was very inefficient because of the poor specificity of the antibody itself. Even in umbilican cord blood only 25% of nucleated red blood cells were labeled as demonstrated by immunogold silver enhancement of transferrin receptor-labeled cells. CONCLUSION: In spite of the availability of a fast and effective separation method (magnetic-activated cell-sorter) the use of the transferrin receptor antigen alone is not likely to enable a reliable identification of fetal cells in maternal circulation. (Am J Obstet Gynecol 1992;166:1350-5.)

Chorionic villus sampling (CVS) is a method of prenatal diagnosis that is usually performed in the first three months of pregnancy. A small sample of tissue from the chorionic villi projections of the placenta are removed for karyotyping, a process of determining the number and configuration of chromosomes. The procedure is safe and the results are rapid and accurate. Although adequate prenatal diagnosis can be obtained by CVS performed in second and third trimester of pregnancy, its use has been limited. Cordocentesis, a direct method of assessing fetal well-being by obtaining blood samples from the fetus' umbilical cord, is the accepted method of late prenatal diagnosis. However, cordocentesis can be technically difficult in pregnancies complicated by abnormal amounts of amniotic fluid, and results take longer to obtain. Fast results may be needed to direct immediate obstetrical decisions. The value of late CVS in diagnosing complications in pregnancies with fetal anomalies and abnormal volume of amniotic fluid, was studied in a total of 301 pregnancies, 225 initially described by suspicious ultrasound. The most common finding (38 percent) on ultrasound was a change in the amount of amniotic fluid; 22 percent of those cases had abnormal findings when CVS samples were karyotyped. Late CVS is useful in providing rapid and accurate results in the presence of suspicious ultrasound imaging of the fetus. (Consumer Summary produced by Reliance Medical Information, Inc.)

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1)and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype–genotype correlations during fetal development.

Neue Schlüsseltechnologien führen gegenwärtig zu einem grundlegenden Wandel im klinischen Einsatz genetischer Labordiagnostik. In der Pränataldiagnostik hat die nicht invasive Abklärung von Aneuploidien im mütterliche Blut Fuß gefasst (NIPT) und dieser Ansatz wird in Zukunft auch bei anderen Chromosomenstörungen und Fragestellungen (monogene Erkrankungen) zum Einsatz kommen. Im postnatalen Bereich hat die Microarray Analyse (Array-CGH, molekulare Karyotypisierung) die konventionelle Chromosomenanalyse bei der Abklärung von Kindern mit Fehlbildungen, einer nicht-syndromalen geistigen Behinderung oder Autismusspektrumstörung abgelöst. Die neuen Hochdurchsatzsequenziermethoden erlauben die effiziente Abklärung von genetisch sehr heterogenen Krankheitsbildern wie z. B. Epilepsien, neuromuskuläre Erkrankungen und Schwerhörigkeit, durch Diagnostik-Panels, bei welchen Dutzende von Genen parallel analysiert werden können. Der Einsatz der Exom oder whole genome Sequenzierung als wissenschaftliche Methode zur Identifizierung von neuen Krankheitsgenen wird auch in der Diagnostik von schweren ungeklärten Erkrankungen oder Entwicklungsstörungen, die genetisch extrem heterogen sind, zum Einsatz kommen. Die neuen Methoden werden die klinische Diagnostik in der Pädiatrie und anderen Bereichen der Medizin über kurz oder lang verändern, indem die genetische Labordiagnostik eher früher im Abklärungsprozess zur Anwendung kommen wird (genetics first).

Interstitial deletions of 1q4 are rare and present with different deletion breakpoints and variable phenotype. We report on the clinical and molecular cytogenetic findings in a girl with minor anomalies, midline defects including prenatally ascertained agenesis of the corpus callosum, epilepsy and developmental delay. A de novo 5.45 Mb deletion almost exclusively located within 1q42 was found to cause this phenotype, which shows significant overlap with the microdeletion 1q41q42 syndrome reported in a few patients except for the agenesis of the corpus callosum. However, deletions in patients with the 1q41q42 syndrome mainly extend into the 1q41 region with a region of overlap including the DISP1gene involved in the SHH pathway, which is not part of the 1q42 deletion in our patient. We suggest that an interaction of genes involved in pathways of embryonic development rather than haploinsufficiency of single genes in the socalled critical regions is causing complex malformation syndromes due to cytogenetic microaberrations in the 1q4 region. © 2010 WileyLiss, Inc.

We report on the clinical and cytogenetic findings as well as the arraybased characterization of an interstitial familial 13q21 deletion initially recognized by standard karyotyping. Although 13q deletions are known to imply a wide variability of clinical consequences, the deletion carriers of the familial deletion in three generations did not reveal a relevant phenotype. The breakpoints and the deletion size in all three carrier individuals were determined by molecular karyotyping confirming a large 14.5 Mb deletion encompassing the 13q21.1–13q21.33 region identical in all three carriers. Gene paucity and the lack of dosagesensitive genes in the delineated region might explain the apparently innocuous nature of this chromosomal anomaly. The example of this family presents evidence for describing the chromosomal region 13q21.1–13q21.33 as a large euchromatic variant or benign copy number variation without phenotypic consequences. Our data underline the importance of a phenogenetic approach combining clinical and laboratory evidence in the interpretation of segmental chromosomal anomalies especially in genetic counseling related to prenatal diagnosis. © 2009 WileyLiss, Inc.

No Abstract.

Ongoing trends in prenatal diagnosis aim at early, rapid, and ideally noninvasive diagnosis as well as at the improvement of risk-screening for aneuploidy. Interphase-fluorescence in situ hybridization and quantitative fluorescence polymerase chain reaction are efficient tools for the rapid exclusion of selected aneuploidies in addition to the established direct preparation of chromosomes from chorionic villi. Interphase fluorescence in situ hybridization has also made possible the diagnosis of selected chromosome abnormalities in single cells (e.g. in preimplantation genetic diagnosis) or noninvasive diagnosis. More complex multicolor fluorescence in situ hybridization approaches are currently being evaluated. Single cell polymerase chain reaction is the key technique for the molecular diagnosis of a growing number of monogenic conditions before implantation or, still more experimental, in fetal cells retrieved from the maternal circulation. New sources for noninvasive diagnosis came into play such as fetal DNA or cell nuclei in maternal plasma. The combination of biochemical parameters in the maternal serum, namely free beta-human chorionic gonadotropin with pregnancy associated plasma protein A and sonographic markers, has already dramatically increased the sensitivity of risk screening in the first trimester of pregnancy.

AbstractPartial trisomy 1q is rare and mostly the result of an abnormal segregation of parental translocation chromosomes and their homologues. Only 31 cases have been described with purepartial trisomy 1q. In the fetus presented, chromosome analysis after amniocentesis had shown an unbalanced male karyotype with an aberrant chromosome 1. A de novo terminal duplication of the long arm was suspected but could not be verified by FISH in 1994. Five years after fetal death, retrospective identification of the additional material in 1q could finally be achieved by comparative genomic hybridization (CGH) using DNA extracted from formalin-fixed and paraffin-embedded fetal tissues. A direct duplication dir dup (1)(pter→q44::q32.1→qter) was found. Only 6 other individuals with duplication of this segment have been described so far. Comparative delineation of a dup1q phenotype with regard to size and origin of the dup (1q) segment evidenced that large duplications as well as proximal and interstitial duplications coincide with more severe visceral malformations, severe mental retar- dation and a short life span. Terminal duplications (1q32→qter) concur with less severe malformations and longer periods of survival, but marked mental retardation. With small terminal duplications (1q42→qter) dysmorphisms are usually mild and intellectual performance is mostly in the normal range.Copyright © 2001 S. Karger AG, Basel

Over the past 9 years we counseled 55 couples whose unborn child was found to carry a sex chromosome polysomy. We performed a survey of postcounseling parental decisions about continuation or termination of these pregnancies. Of the 55 embryos or fetuses, 23 had the karyotype 47,XXY, 10 had 47,XYY, and 12 had 47,XXX. In addition, there were 10 instances of true mosaicism, i.e. 47,XXY/46,XY (n = 5), 47,XYY/46,XY (n = 2), or 47,XXX/46,XX (n = 3). Mean gestational age (± standard deviation) at diagnosis was 18.3 ± 3.0 weeks. After comprehensive genetic counseling 48 (87.3%) of these pregnancies were carried to term. In seven cases (12.7%) the parents elected a pregnancy termination. Two of 31 pregnancies (6.5%) primarily ascertained at our center were aborted, whereas amongst the 24 referred cases, 5 couples (20.8%) opted for a termination. The mean gestational age of the terminated pregnancies was 19.7 weeks. The overall termination rate of 12.7% appears low in comparison with literature data. Most reports from other institutions present termination rates between 32 and 66%. The reason for the low rate of induced abortions in our study cohort is not clear. Cultural differences in parental perception of sex chromosomal polysomies may be of importance, and peculiarities of genetic counseling at our institution could also play a role. Although counseling was nondirective, we did put emphasis on providing prospective parents with information from unbiased follow-up studies of children with Klinefelter syndrome and other sex chromosome polysomies. Am. J. Med. Genet. 80:330–334, 1998. © 1998 Wiley-Liss, Inc.

PROBLEM: The need for an inexpensive and reproducible technique for noninvasive prenatal diagnosis by fetal cell isolation from maternal blood.

Lissencephaly is a sign of various genetic and non-genetic conditions and a constant feature in the socalled lissencephaly syndromes. Type I lissencephaly in the Miller-Dieker syndrome (MDS) and the isolated lissencephaly sequence (ILS) is differentiated from type II lissencephaly in the Walker-Warburg (hydrocephalus, agyria, retinal dysplasia with or without encephalocele, HARD±E) syndrome and related conditions (e.g. muscle-eye-brain syndrome). In about 90% of patients with MDS structural defects have been confirmed in the short arm of chromosome 17 (p13.3), detectable by classical cytogenetic methods, fluorescence in situ hybridisation (FISH), or molecular genetic techniques. The identification of unbalanced inversions and translocations is of particular importance because of the risk of their recurrence, while deletions and ring chromosomes are mainly sporadic. Recently, submicroscopic deletions have also been reported in ILS, providing evidence that lissencephaly in MDS and ILS is caused by deletions of the same gene(s) in 17p13.3 and that MDS may be considered to be a “contiguous gene syndrome.” Syndromes featuring lissencephaly type II (HARD±E and related conditions) are most probably autosomal-recessively inherited. Neither the location of the genes involved nor the nature of the mutations are known at present. It is also unknown whether HARD±E and muscle-eye-brain syndrome are allelic.