Consanguinity and pregnancy outcomes in a multi-ethnic, metropolitan European population

Objective: The aim of the present study was to assess the risk of major anomalies in the offspring of consanguineous couples, including data on the prenatal situation. Methods: Over 20years (1993-2012), 35391 fetuses were examined by prenatal sonography. In 675 cases (1.9%), parents were consanguineous, with 307 couples (45.5%) related as first cousins, 368 couples (54.5%) beyond first cousins. Detailed information was retrieved on 31710 (89.6%) fetuses, (consanguineous 568: 1.8%). Results: Overall prevalence of major anomalies among fetuses with non-consanguineous parents was 2.9% (consanguineous, 10.9%; first cousins, 12.4%; beyond first cousins, 6.5%). Adjusting the overall numbers for cases having been referred because of a previous index case, the prevalences were 2.8% (non-consanguineous) and 6.1% (consanguineous) (first cousin, 8.5%; beyond first cousin, 3.9%). Further adjustment for differential rates of trisomic pregnancies indicated 2.0%/5.9% congenital anomalies (non-consanguineous/consanguineous groups), that is, a consanguinity-associated excess of 3.9%, 6.1% in first cousin progeny and 1.9% beyond first cousin. Conclusions: The prevalence of major fetal anomalies associated with consanguinity is higher than in evaluations based only on postnatal life. It is important that this information is made available in genetic counselling programmes, especially in multi-ethnic and multi-religious communities, to enable couples to make informed decisions

The First Neocentric, Discontinuous, and Complex Small Supernumerary Marker Chromosome Composed of 7 Euchromatic Blocks Derived from 5 Different Chromosomes

Background: The majority of small supernumerary marker chromosomes (sSMCs) are derived from one single chromosome. Complex sSMCs instead consist of two to three genomic segments, originating from different chromosomes. Additionally, discontinuous sSMCs have been seen; however, all of them are derived from one single chromosome. Here, we reported a 41 year-old patient with infertility, hypothyroidism, rheumatism, and degenerative spine and schizoaffective disorder, being a carrier of a unique, complex, and discontinuous sSMC. Methods: The sSMC was characterized in detail by banding and molecular cytogenetics including fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (aCGH), as well as by optical genome mapping (OGM). Results: The neocentric sSMC characterized here contained seven portions of five different chromosomes and was present in ~50% of both peripheral blood cells and buccal mucosa cells. aCGH and OGM revealed gains of 8q12.3q12.3, 8q22.3–8q23.1, 9q33.3–9q34.11, 14q21.1–14q21.1, 14q21.1–14q21.2, 15q21.2–15q21.2, and 21q21.1–21q21.1. Furthermore, glass-needle based microdissection and reverse FISH, as well as FISH with locus-specific probes confirmed these results. The exact order of the involved euchromatic blocks could be decoded by OGM. Conclusions: Among the >7000 reported sSMCs in the literature, this is the only such complex, discontinuous, and neocentric marker with a centric minute shape

Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure.

PURPOSE: Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone. EXPERIMENTAL DESIGN: Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response. RESULTS: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 +/- 5% decrease (P 42%) after 2 weeks (P < or = 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (-21% to -70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 +/- 4%), tumor blood volume (50 +/- 6%), and vessel diameter (40 +/- 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged. Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005). CONCLUSIONS: Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy