A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

<p>Abstract</p> <p>Background</p> <p>Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date.</p> <p>Methods</p> <p>We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents.</p> <p>Results</p> <p>Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial <it>de novo </it>1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping.</p> <p>Conclusion</p> <p>The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.</p

Clostridium difficile infection.

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota

Population Enumeration and Household Utilization Survey Methods in the Enterics for Global Health (EFGH): Shigella Surveillance Study

Background: Accurate estimation of diarrhea incidence from facility-based surveillance requires estimating the population at risk and accounting for case patients who do not seek care. The Enterics for Global Health (EFGH) Shigella surveillance study will characterize population denominators and healthcare-seeking behavior proportions to calculate incidence rates of Shigella diarrhea in children aged 6–35 months across 7 sites in Africa, Asia, and Latin America. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will use a hybrid surveillance design, supplementing facility-based surveillance with population-based surveys to estimate population size and the proportion of children with diarrhea brought for care at EFGH health facilities. Continuous data collection over a 24 month period captures seasonality and ensures representative sampling of the population at risk during the period of facility-based enrollments. Study catchment areas are broken into randomized clusters, each sized to be feasibly enumerated by individual field teams. Conclusions: The methods presented herein aim to minimize the challenges associated with hybrid surveillance, such as poor parity between survey area coverage and facility coverage, population fluctuations, seasonal variability, and adjustments to care-seeking behavior

Substitutional Effects on the Electromechanical Properties of Lead-free, Piezoelectric (Na₀.₅Bi₀.₅)TiO₃-BaTiO₃ (NBT-BT)

This work investigates the effect of cation substitution on the properties of the lead-free, solid solution (Na₀.₅Bi₀.₅)TiO₃-BaTiO₃ (NBT-BT). Substitution into NBT-BT increases disorder and increases the relaxor ferroelectric properties. These relaxor ferroelectric materials show large piezoelectric strains that can be utilized in actuator applications. Ceramic samples were prepared using standard solid-state synthesis techniques using metal oxide and carbonate reagents. Materials were pressed and sintered into ceramic disks. All prepared NBT-BT materials had their structure investigated via powder x-ray diffraction. Electrical properties such as, dielectric permittivity, ferroelectricity, and piezoelectricity, were investigated and analyzed for each prepared material. Three new group 13-substituted NBT-BT materials were prepared and analyzed to determine any periodic trends: (Na₀.₅Bi₀.₅)TiO₃-0.055BaTiO₃-Bi(M)O₃ M=Al, Ga, In. The ternary phases selected were theoretically determined to have high ferroelectric properties and were substituted in molar amounts of 0.02, 0.04 Bi(Al)O₃, 0.02, 0.04 Bi(Ga)O₃, and 0.01, 0.02 Bi(In)O₃. Powder x-ray and neutron diffraction experiments suggests that all materials had a complex, two-phase structure with a mixture of tetragonal P4bm and monoclinic Cc phases. Most substituted NBT-BT samples displayed modest electrical properties improvements compared to the unmodified, NBT-BT. The 2% BiGaO₃ substituted sample displayed the highest room temperature and overall dielectric permittivity (Ɛᵣ = 6626 at 259 °C) with the second highest strain performance (d₃₃* = 570 pm/V). The 4% BiAlO3 substituted sample uniquely underwent a reversible ergodic relaxor to ferroelectric phase transition which enhanced the large field strain (d₃₃* = 695 pm/V). This project is described further in Chapter 3. The ternary, solid solution of lead-free (Na₀.₅Bi₀.₅)TiO₃-BaTiO₃ (NBT-BT) and nonpolar BiGaO₃ (NBT-xBT-yBG) were systematically prepared and investigated. Samples were prepared near the morphotropic phase boundary (MPB) of NBT-BT ((1-x)NBT-xBT, x= 0.04-0.09) with 2-7% BiGaO₃ substitution. Dielectric, ferroelectric, and piezoelectric properties were analyzed for all prepared samples. A phase diagram was prepared by determining the ferroelectric to ergodic relaxor transition temperature (TF-R) via dielectric permittivity measurements on poled samples. The enhanced strain at the electric field induced relaxor to ferroelectric transition was investigated to determine which composition around the MPB displayed the largest strain performance. The highest strain achieved was near the MPB of the binary parent, 0.93NBT-0.07BT, substituted with 4% BiGaO₃(0.53 % , d33* = 883 pm/V). The largest strains for each system occurred in compositions with one to two percent BiGaO₃ past the RT ferroelectric to relaxor transition. These results reveal, similar to that of MPB properties, that the largest electric field enhanced strain occurs near the MPB of the binary NBT-BT in substituted NBT-BT. Chapter 4 contains further details on this study

22q11.2 Distal Deletion: A Recurrent Genomic Disorder Distinct from DiGeorge Syndrome and Velocardiofacial Syndrome

Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent ∼3 Mb deletion or a smaller, less common, ∼1.5 Mb nested deletion. Both deletions apparently occur as a result of homologous recombination between nonallelic flanking low-copy repeat (LCR) sequences located in 22q11.2. Interestingly, although eight different LCRs are located in proximal 22q, only a few cases of atypical deletions utilizing alternative LCRs have been described. Using array-based comparative genomic hybridization (CGH) analysis, we have detected six unrelated cases of deletions that are within 22q11.2 and are located distal to the ∼3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a ∼1.4 Mb or ∼2.1 Mb recurrent deletion flanked proximally by LCR22-4 and distally by either LCR22-5 or LCR22-6, respectively. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents (11 out of 12 were available) had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was prevalent among the patients. Two patients were found to have a cardiovascular malformation, one had truncus arteriosus, and another had a bicuspid aortic valve. A single patient had a cleft palate. We conclude that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes