Atrioventricular canal defect and genetic syndromes: the unifying role of sonic hedgehog

The atrioventricular canal defect (AVCD) is a congenital heart defect (CHD) frequently associated with extracardiac anomalies (75%). Previous observations from a personal series of patients with AVCD and "polydactyly syndromes" showed that the distinct morphology and combination of AVCD features in some of these syndromes is reminiscent of the cardiac phenotype found in heterotaxy, a malformation complex previously associated with functional cilia abnormalities and aberrant Hedgehog (Hh) signaling. Hh signaling coordinates multiple aspects of left-right lateralization and cardiovascular growth. Being active at the venous pole the secondary heart field (SHF) is essential for normal development of dorsal mesenchymal protrusion and AVCD formation and septation. Experimental data show that perturbations of different components of the Hh pathway can lead to developmental errors presenting with partially overlapping manifestations and AVCD as a common denominator. We review the potential role of Hh signaling in the pathogenesis of AVCD in different genetic disorders. AVCD can be viewed as part of a "developmental field," according to the concept that malformations can be due to defects in signal transduction cascades or pathways, as morphogenetic units which may be altered by Mendelian mutations, aneuploidies, and environmental causes

9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression

Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible gene is EHMT1. A 9q34 duplication syndrome (9q34 DS) had been reported in literature, but it has never been characterized by a detailed molecular analysis of the gene content and endpoints. To the best of our knowledge, we report on the first patient carrying the smallest 9q34.3 duplication containing EHMT1 as the only relevant gene. We compared him with 21 reported patients described here as carrying 9q34.3 duplications encompassing the entire gene and extending within ~\u20093 Mb. By surveying the available clinical and molecular cytogenetic data, we were able to discover that similar neurodevelopmental disorders (NDDs) were shared by patient carriers of even very differently sized duplications. Moreover, some facial features of the 9q34 DS were more represented than those of KS. However, an accurate in silico analysis of the genes mapped in all the duplications allowed us to support EHMT1 as being sufficient to cause a NDD phenotype. Wider patient cohorts are needed to ascertain whether the rearrangements have full causative role or simply confer the susceptibility to NDDs and possibly to identify the cognitive and behavioral profile associated with the increased dosage of EHMT1

De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder

2002 Wild Blueberry Project Reports

The 2002 edition of the Wild Blueberry Project Reports was prepared for the Wild Blueberry Commission of Maine and the Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Factors Affecting Microbial and Pesticide Residue Levels on Wild Blueberries 2. Effect of Blueberry Products on Oxidation in Meat Based Food 3. Determination of Pesticide Residue Levels in Freshly Harvested and Processed Wild Blueberries 4. Detection of Infested Wild Blueberries using Near-Infrared Spectroscopy 5. Investigation Of The Mechanism By Which Blueberry Fractions Maintain Arterial Integrity 6. Antioxidant Assessment in the Elderly 7. Water Use of Wild Blueberries and the Impact of Plant Water Stress on Yield 8. Control Tactics for Wild blueberry Pest Insects 9. IPM Strategies 10. Pest Biology 11. Wild Blueberry Pollination Research 12. Survey and Determination of Effective Control of Stem Blight and Leaf Spot Diseases in Wild Blueberry Fields 13. Effect of Foliar-applied Iron Chelate Concentration on Leaf Iron Concentration, Wild Blueberry Growth and Yield 14. Effect of Boron Application Methods on Boron Uptake in Wild Blueberries 15. Effect of Foliar N spray on Leaf N Concentration, Growth and Yield of Wild Blueberries 16. Effect of Foliar Spray (4-13-15) on Leaf Nutrient Concentration, Growth and Yield of Wild Blueberries 17. Effect of Foliar Copper Application on Growth and Yield of Wild Blueberries 18. Effect of Foliar Copper and/or Iron Application on Growth and Yield of Wild Blueberries 19. Effect of Soil pH on Nutrient Uptake 20. Assessment of Hexazinone Alternatives for Weed Control in Wild Blueberries and Weed Control 21. Evaluation of Fall Applications of Sulfonylurea Herbicides for Bunchberry Control in Wild Blueberries 22. Evaluation and Demonstration of Techniques for Filling in Bare Spots in Wild Blueberry Fields 23. Blueberry Extension Education Program Base 24. 2002 Pesticide Groundwater Survey 25. Cultural Weed Management using sulfur to lower the p

2001 Wild Blueberry CSREES Project Reports

The 2001 edition of the Wild Blueberry CSREES Progress Reports was prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Effect of Wild Blueberry Products on Oxidation in Meat Based Food Systems 2. Factors Affecting the Microbial and Pesticide Residues Levels on Wild Blueberries 3. Determination of Pesticide Residue Levels in Fresh and Processed Wild Blueberries 4. Separation of Maggot-Infested Wild Blueberries in the IQF Processing Line 5. Water Use of Wild Blueberries and the Impact of Plant Water Stress on Yields 6. Survey of Stem Blight and Leaf Spot Diseases in Wild Blueberry Fields 7. IPM Strategies 8. Control Tactics for Wild Blueberry Pest Insects, 2001 9. Biology and Ecology of Blueberry Pest Insects 10. Diurnal Bee Activity and Measurement of Honeybee Field Strength 11. Effect of Foliar-applied Iron (Fe) Chelate Concentration on Leaf Iron Concentration, Wild Blueberry Growth and Yield 12. Effect of Boron Application Methods on Boron Uptake in Wild Blueberries 13. Effect of Foliar Iron and Copper Application on Growth and Yield of Wild Blueberries 14. Effect of Fertilizer Timing on Wild Blueberry Growth and Productivity 15. Effect of Foliar Copper Application on Growth and Yield of Wild Blueberries 16. Effect of Prune-year Applications of Nutri-Phitetm P or Nutri-Phitetm P+K on Growth and Yield of Wild Blueberry (Vaccinium angustifolium Ait.) 17. Effect of Soil pH on Nutrient Uptake 18. Assessment of Azafenidin for Weed Control in Wild Blueberries 19. Assessment of Rimsulfuron for Weed Control in Wild Blueberries 20. Assessment of Pendimethalin for Weed Control in Wild Blueberries 21. Evaluation and Demonstration of Techniques for Filling in Bare Spots in Wild Blueberry Fields 22. Assessment of Sprout-less Weeder for Hardwood Control in Wild Blueberries 23. Wild Blueberry Extension Education Program in 2001 24. Evaluation of Fungicide Efficacy in Wild Blueberry Fields 25. 2001 Pesticide Groundwater Survey 26. Cultural Weed Management Using Sulfur to Lower the pH 27. Wild Blueberry Web Sit

2000 Wild Blueberry Project Reports

The 2000 edition of the Wild Blueberry Project Reports was prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Determination of Pesticide Residue Levels in Fresh and Processed Wild Blueberries 2. Factors Affecting the Microbiological Quality of IQF Blueberries 3. Effect of Processed Blueberry Products on Oxidation in Meat Based Food Systems 4. Separation of Maggot Infested Wild Blueberries in the IQF Processing Line 5. Water Use of Wild Blueberries 6. Control Tactics for Blueberry Pest Insects, 2000 7. IPM Strategies 8. Biology and Ecology of Blueberry Pest Insects 9. Survey of Stem Blight and Leaf Spot Diseases in Lowbush Blueberry Fields 10. Phosphorus/Nitrogen Fertilizer Ratio 11. Effect of Boron Application Methods on Boron Uptake in Lowbush Blueberries 12. Effect of Foliar Iron and Copper Application on Growth and Yield of Lowbush Blueberries 13. Effect of Soil pH on Nutrient Uptake 14. Effect of Nutri-Phite (tm) P+K on Growth and Yield of Lowbush Blueberry 15. Effect of Fertilizer Timing on Lowbush Blueberry Growth and Productivity 16. Assessment of Azafenidin for Weed Control in Wild Blueberries 17. Assessment of Rimsulfuron for Weed Control in Wild Blueberries 18. Assessment of Pendimethalin for Weed Control in Wild Blueberries 19. Assessment of VC1447 for Weed Control in Wild Blueberries 20. Cultural Management Using pH for Weed Control in Wild Blueberries 21. Evaluation of Sprout-Less Weeder® for Weed Control in Wild Blueberries 22. Evaluation of RoundUp Ultra® and Touchdown 5® for Weed Control in Wild Blueberries 23. Evaluation and Demonstration of Techniques for Filling in Bare Spots in Wild Blueberry Fields 24. Evaluation of Fungicides Efficacy in Wild Blueberry Fields 25. Velpar® and Sinbar/Karmex® Demonstration Plot Comparison Trial 26. Blueberry Extension Education Program in 2000 27. 2000 Hexazinone Groundwater Surve

2003 Wild Blueberry Project Reports

The 2003 edition of the Wild Blueberry Project Reports was prepared for the Wild Blueberry Commission of Maine and the Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Factors Affecting the Microbial and Pesticide Residues Levels on Lowbush Blueberries 2. Effect of Blueberry Products on Oxidation in Ground Beef Patties 3. Infestation Detection using Near-Infrared Spectroscopy 4. Whole Wild Blueberries and Arterial Functional Properties 5. Irrigation Water use in Wild Blueberry Production 7. Control Tactics for Blueberry Pest Insects 8. IPM Strategies 9. Biology and Ecology of Blueberry Pest Insects, 2003 10. Wild Blueberry Pollination Research 11. Stem Blight/Dieback and Leaf Spot Diseases in Wild Blueberry Fields 12. Effect of Foliar N spray on Leaf N Concentration, Growth and Yield of Wild Blueberries 13. Effect of Foliar Spray (4-13-15) on Leaf Nutrient Concentration, Growth and Yield of Wild Blueberries 14. Effect of Foliar Copper Application on Growth and Yield of Wild Blueberries 15. Effect of Foliar Copper and/or Iron Application on Growth and Yield of Wild Blueberries 16. Effect of Soil pH on Nutrient Uptake. 17. Effect of Gibberellic Acid (GA3) and CPPU on Fruit Set and Yield of Wild Blueberry after low temperature flower stress 18. Effect of Fertilizer Timing (prune year vs. crop year) on Wild Blueberry Growth and Productivity. 19. Assessment of Hexazinone Alternatives for Weed Control in Wild Blueberries and Weed Control and Field Cover Program Base 20. Evaluation of Fall Applications of Sulfonylurea Herbicides for Bunchberry Control in Wild Blueberries 21. Assessment of clean-cut adapter on hand clippers for weed control in wild blueberries 22. Evaluation and Demonstration of Techniques for Filling in Bare Spots in Wild Blueberry Fields 23. Blueberry Extension Education Program in 2003 24. 2003 Pesticide Groundwater Survey 25. Cultural Weed Management using Sulfur to lower the p

2011 Wild Blueberry Project Reports

The 2011 edition of the Wild Blueberry Project Reports was prepared for the Wild Blueberry Commission of Maine and the Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Mechanisms through which wild blueberries affect functional characteristics of the arterial wall related to endothelial dysfunction in Spontaneously Hypertensive Rats 2. Do wild blueberries affect high blood lipids, high blood glucose and obesity as related to the Metabolic Syndrome? 3. Control tactics for blueberry pest insects, 2011 4. IPM strategies, 2011 5. Biology and ecology of pest insects, 2011 6. Biology and ecology of beneficial insects, 2011 7. Pesticide residues on lowbush blueberry, 2011 8. Maine wild blueberry –mummy berry research and extension 9. Valdensinia leaf spot – Education, control and research – 2011 10. Effect of soil pH on nutrient uptake 11. Evaluation of several growth regulators for stimulating lowbush blueberry rhizome production 12. Evaluation of the effects of Gypsum (CaSO4) on wild blueberry fruit Ca concentration 13. Fall application of tribenuron methyl for bunchberry control in wild blueberries, 2009-2011 – effects of fall versus spring pruning on cover and yield in the crop year (final report) 14. Wild Blueberry Extension Education Program in 2011 INPUT SYSTEMS STUDY: 15. Systems approach to improving the sustainability of wild blueberry production, Year 2 of a four-year study – experimental design 16. The effects of different agronomic practices on the composition and quality of wild blueberries 17. Systems approach to improving the sustainability of wild blueberry production, Year 2 of a four-year study, blueberry quality from the first harvest year 18. Food safety- Prevalence study of Escherichia coli O157:H7, Listeria monocytogenes and Salmonella spp. on lowbush blueberries (Vaccinium angustifolium) 19. Abundance of insect pest species and natural enemies in lowbush blueberry fields maintained under different management practices 20. Systems approach to improving the sustainability of wild blueberry production, Year 2 of a four-year study, disease management results 21. Systems approach to improving the sustainability of wild blueberry production, Year 2 of a four-year study, weed management results 22. Systems approach to improving sustainability of wild blueberry production, Year 1 of a four-year study, preliminary soil health and chemistry results 23. Management effects on the phosphorus chemistry of wild blueberry barrens soil 24. Systems approach to improving the sustainability of wild blueberry production, preliminary economic comparison 2010-2011 25. Transition to organic production Year 2: Evaluation of gypsum and bone char 26. The effect of field management, forest edge composition, and field location on insect-mediated ecosystem services (scavenging/predation) (ancillary study) 27. Pre-emergent combinations of herbicides for weed control in wild blueberry fields (ancillary study) 28. Systems approach to improving the sustainability of wild blueberry production – Ancillary land-leveling study, year 1 (ancillary study) 29. Effects of compost and mulch on soil health and soil nutrient dynamics in wild blueberry (ancillary study

Mutation update for the SATB2 gene

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120=42.5%) followed by missense variants (31/120=25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge on animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS

Gillespie syndrome in a South Asian child:a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features

Abstract Background Gillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka. Case presentation A 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene. Conclusion The report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members