Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients. OBJECTIVES: Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study. METHODS: Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study. RESULTS: By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young. DISCUSSION: Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance. CONCLUSIONS: This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore.

Variation in the ICAM1 gene is not associated with severe malaria phenotypes.

Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host intercellular adhesion molecule (ICAM)-1 receptor is important in the pathogenesis of severe malaria. Previous association studies between polymorphisms in the ICAM1 gene and susceptibility to severe malarial phenotypes have been inconclusive and often contradictory. We performed genetic association studies with 15 single nucleotide polymorphisms (SNPs) around the ICAM1 locus. All SNPs were screened in a family study of 1071 trios from The Gambia, Malawi and Kenya. Two key non-synonymous SNPs with previously reported associations, rs5491 (K56M or 'ICAM-1(Kilifi)') and rs5498 (K469E), were tested in an additional 708 Gambian trios and a case-control study of 4058 individuals. None of the polymorphisms were associated with severe malaria phenotypes. Pooled results across our studies for ICAM-1(Kilifi) were, in severe malaria, odds ratio (OR) 1.02, 95% confidence interval (CI) 0.96-1.09, P=0.54, and cerebral malaria OR 1.07, CI 0.97-1.17, P=0.17. We assess the available epidemiological, population genetic and functional evidence that links ICAM-1(Kilifi) to severe malaria susceptibility.

Histology and lectin-binding patterns in the digestive tract of the carnivorous larvae of the anuran, Ceratophrys ornata.

Larvae of Ceratophrys ornata are carnivorous, have relatively short digestive tracts and continue to feed during metamorphic climax, in contrast to those of more typical herbivorous anuran larvae. The present study describes both histological and histochemical changes in the stomach, small intestine, and large intestine of C. ornata prior to and during metamorphic climax. Modifications in these organs were found to be similar to but less dramatic than those in herbivorous larvae. Luminal epithelial cells in the three regions develop vacuoles, suggesting degeneration, but sloughing of this epithelium, as occurs in herbivorous larvae, was not observed in C. ornata. Multicellular tubular glands develop gradually in the gastric area during the larval stages, gastric pits appear during metamorphic climax, and mucous neck cells are first visible in the juvenile. Goblet cells in the small and large intestine increase in number during larval life, as do the number of folds in the intestinal wall. Increase in diameter and thickness of the wall occurs in the stomach as well as in the small and large intestine. Such changes result in an adult-type digestive tract characteristic of frogs in general. Staining with two horseradish peroxidase conjugated lectins, soybean agglutinin (SBA) and Ulex europaeus agglutinin I (UEA I), demonstrated specific sites along the digestive tract of glycoconjugates with terminal sugars N-acetylgalactosamine and alpha-fucose, respectively. As metamorphic climax approaches, staining intensities decrease--thus providing evidence for metamorphic changes in the sugar moieties of glycoconjugates present in the digestive tract of carnivorous larvae.

Workshop 1 (synthesis): relation between industry and other water interests in a catchment context--facilitated stakeholder dialogue.

Workshop 1 considered the nature and identity of water stakeholders and how best to facilitate an open, transparent, democratic process of dialogue leading to agreed strategies to address water problems.

PTPRC (CD45) variation and disease association studied using single nucleotide polymorphism tagging.

CD45 is a haemopoietic tyrosine phosphatase, crucial for lymphocyte signalling. Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases. Using HapMap data, we show that there is substantial linkage disequilibrium across the CD45 gene (PTPRC), with similar patterns in different populations. Employing a set of single nucleotide polymorphisms, correlated with a substantial proportion of variation across this gene, we tested for association with type 1 diabetes, Graves' disease in a Japanese population, hepatitis C in UK population and tuberculin response in a Chinese population. A limited number of common haplotypes was found. Most 138G alleles are present on only one haplotype, which is associated with Graves' disease, supporting previous data that A138G is a functionally important CD45 polymorphism.