YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.Michele Gabriele, Anneke T. Vulto-van Silfhout, Pierre-Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J. Pedurupillay, Petter Stromme, Jill A. Rosenfeld, Yunru Shao, William J. Craigen, Christian P. Schaaf, David Rodriguez-Buritica, Laura Farach, Jennifer Friedman, Perla Thulin, Scott D. McLean, Kimberly M. Nugent, Jenny Morton, Jillian Nicholl, Joris Andrieux, Asbjørg Stray-Pedersen, Pascal Chambon, Sophie Patrier, Sally A. Lynch, Susanne Kjaergaard, Pernille M. Tørring, Charlotte Brasch-Andersen, Anne Ronan, Arie van Haeringen, Peter J. Anderson, Zöe Powis, Han G. Brunner, Rolph Pfundt, Janneke H.M. Schuurs-Hoeijmakers, Bregje W.M. van Bon, Stefan Lelieveld, Christian Gilissen, Willy M. Nillesen, Lisenka E.L.M. Vissers, Jozef Gecz, David A. Koolen, Giuseppe Testa, Bert B.A. de Vrie

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families

Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations

Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families

Data Paper. Data Paper

<h2>File List</h2><div> <p><a href="Individuals.csv">Individuals.csv</a> (MD5: ): Height, condition, location of individual saguaros at plot X</p> <p><a href="NurseInfo.csv">NurseInfo.csv</a> (MD5: ): Nurse plant information at plot X</p> <p><a href="Species.csv">Species.csv</a> (MD5: ): Summary of plant codes and nomenclature of species detected</p> <p><a href="Boundaries.shp">Boundaries.shp</a> (MD5: ): Layer depicting plot boundaries</p> <p>PlotX1908.shp: Layer depicting saguaros surveyed in 1908 that are within plot X (see ShpFiles.zip)</p> <p>All *.shp files are provided as the .zip file <a href="ShpFiles.zip">ShpFiles.zip</a> (MD5: ); all *.csv files can be downloaded at once using <a href="CsvFiles.zip">CsvFiles.zip</a> (MD5: ).</p> </div><h2>Description</h2><div> <p>The saguaro cactus (<i>Carnegiea gigantea</i>) is one of the most iconic perennials in the Sonoran Desert. The ecological importance of this species has motivated studies that explored its physiological adaptations to deserts, factors controlling its recruitment and distribution, and changes in its population density and extent over time. The population of saguaros on Tumamoc Hill (Tucson, Arizona) is one of the best studied. Saguaros on and nearby Tumamoc Hill were mapped in 1908, and in 1964 R. M. Turner and J. R. Hastings established four 250-m wide plots within the original census area. Plots were established on the north, south, east, and west-facing slopes of Tumamoc Hill, and each plot extends from the top to the base of the hill. Plots were resurveyed in 1970, 1987, 1993, and between 2010 and 2012. In this data paper, we present all information associated with this monitoring program, which includes digital versions of Spalding’s original 1908 saguaro map as well as information regarding individual saguaros located in each of the four plots. Collected data include plant height, number of branches, and plant condition, as well as plant location. Starting in 1993, we also noted the identity and condition of plant species growing in close proximity to each saguaro. The archived data set described here contains information pertaining to >5800 saguaros.<br> Past analyses of these data include reconstructions of regeneration patterns from observed age structures and the determination of the average height-specific growth rates for plants on each slope. The findings from these studies have broadened our understanding of the relationship between saguaro regeneration patterns and climate. These data have also provided pivotal information regarding regional trends of saguaro populations throughout the Sonoran Desert. As a group, the Tumamoc Hill censuses constitute one of the longest spatially explicit monitoring efforts for a single species in the world.  They provide an observational baseline for future comparisons relating individual growth and population demographics to rising CO2 levels, climate change, vegetation change, or changes in other biotic or abiotic factors.   </p> <p> <i>Key words</i>: Carnegiea gigantea;<i> long-term monitoring; permanent plots; population dynamics; saguaro cactus; Sonoran Desert; spatially explicit data</i>. </p> </div

Glycogen storage disease type Ia: Current management options, burden and unmet needs

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed

Human KCNQ5 de novo Mutations Underlie Epilepsy and Intellectual Disability

We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID) and/or epilepsy by whole-exome sequencing. These variants comprised of two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman, et al., 2017). Surprisingly, all eight missense variants resulted in gain-of-function (GOF) due to hyperpolarized voltage-dependence of activation or slowed deactivation kinetics, while the two nonsense variants were confirmed to be loss-of-function (LOF). One severe GOF allele (P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: Milder presentations with LOF or smaller GOF shifts in voltage-dependence (DV50= ~-15 mV), and severe presentations with larger GOF shifts in voltage-dependence (DV50= ~-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created using CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures, and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Item does not contain fulltextPURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting