Evaluation of fetal cerebral blood flow perfusion using power Doppler Ultrasound Angiography (3D-PDA) in growth-restricted fetuses

Objective: to explore the potential of 3D Power Doppler Angiography (3D PDA) to evaluate the cerebral circulation in normal and growth restricted fetuses (IUGR). Study design: in a pilot study, we enrolled 51 appropriate for gestational age (AGA) pregnancies and 17 singleton pregnancies presenting IUGR, all between 22 and 38 weeks of gestation. Using 3D power Doppler ultrasound, a volume acquisition of the fetal brain was performed. Two regions of interest (ROI) were defined within the fetal brain. Zone 1 is anterior to the cavum septi pellucidi (CSP). Zone 2 is defined by a rectangle obtained tracing a contour between the temporal bones as wide as the CSP, corresponding to the area of the middle cerebral artery. The Flow Index (FI), the Vascularization Index (VI), the Vascularization and Flow Index (VFI) were determined in both areas in both IUGR and AGA fetuses by a single operator. IUGR fetuses were divided into three groups: Group 1, with normal pulsatility index (PI) of umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV); Group 2, IUGR fetuses with abnormal UA PI, normal MCA PI, normal DV PI; in Group 3, IUGR fetuses with abnormal UA PI, MCA PI and DV PI. Results: FI and VFI values of zone 1 were increased in Group 1.Values of VFI in zone 2 were increased in Group 2. Conclusions: Our findings are in line with recent studies in growth-restricted fetuses suggesting that the anterior cerebral artery shows Doppler signs of vasodilatation before these are observed in the MCA, demonstrating the “frontal brain sparing effect”

Developing a policy for paediatric biobanks: Principles for good practice

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the <i>FMR1</i> Gene.

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the &lt;i&gt;FMR1&lt;/i&gt; gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected

Judging in the Genomic era: judges’ genetic knowledge, confidence and need for training

Genetic information is increasingly used in many contexts, including health, insurance, policing and sentencing – with numerous potential benefits and risks. Protecting from the related risks requires updates to laws and procedures by justice systems. These updates depend to a large extent on what the key stakeholders – the judiciary – know and think about the use of genetic information. This study used a battery of 25 genetic knowledge items to collect data from 73 supreme court judges from the same country (Romania) on their knowledge of genetic information. Their responses were compared with those of two other groups: lawyers (but not judges; N = 94) and nonlawyers (N = 116) from the same country. The data were collected at approximately the same time from the three groups. The judges’ results were also compared to the results obtained from a general population data collection (N = 5310). The results showed that: 1) judges had overall better knowledge of genetics than the other groups, but their knowledge was uneven across different genetic concepts; 2) judges were overall more confident in their knowledge than the other two groups, but their confidence was quite low; and 3) the correlation between knowledge and confidence was moderate for judges, weak for lawyers and not significant for non-lawyers. Finally, 100% of the judges agreed that information on gene-environment processes should be included in judges’ training. Increasing genetic expertise of the justice stakeholders is an important step towards achieving adequate legal protection against genetic data misuse

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

Symplectic lattice gauge theories in the grid framework: Approaching the conformal window

Symplectic gauge theories coupled to matter fields lead to symmetry enhancement phenomena that have potential applications in such diverse contexts as composite Higgs, top partial compositeness, strongly interacting dark matter, and dilaton-Higgs models. These theories are also interesting on theoretical grounds, for example in reference to the approach to the large-N limit. A particularly compelling research aim is the determination of the extent of the conformal window in gauge theories with symplectic groups coupled to matter, for different groups and for field content consisting of fermions transforming in different representations. Such determination would have far-reaching implications, but requires overcoming huge technical challenges. Numerical studies based on lattice field theory can provide the quantitative information necessary to this endeavor. We developed new software to implement symplectic groups in the Monte Carlo algorithms within the Grid framework. In this paper, we focus most of our attention on the Sp(4) lattice gauge theory coupled to four (Wilson-Dirac) fermions transforming in the 2-index antisymmetric representation, as a case study. We discuss an extensive catalog of technical tests of the algorithms and present preliminary measurements to set the stage for future large-scale numerical investigations. We also include the scan of parameter space of all asymptotically free Sp(4) lattice gauge theories coupled to varying number of fermions transforming in the antisymmetric representation