De novoframeshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies

BACKGROUND: Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders. CASE PRESENTATION: We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3, predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon. CONCLUSIONS: We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly

Dependence of climate response on meridional structure of external thermal forcing

This study shows that the magnitude of global surface warming greatly depends on the meridional distribution of surface thermal forcing. An atmospheric model coupled to an aquaplanet slab mixed layer ocean is perturbed by prescribing heating to the ocean mixed layer. The heating is distributed uniformly globally or confined to narrow tropical or polar bands, and the amplitude is adjusted to ensure that the global mean remains the same for all cases. Since the tropical temperature is close to a moist adiabat, the prescribed heating leads to a maximized warming near the tropopause, whereas the polar warming is trapped near the surface because of strong atmospheric stability. Hence, the surface warming is more effectively damped by radiation in the tropics than in the polar region. As a result, the global surface temperature increase is weak (strong) when the given amount of heating is confined to the tropical (polar) band. The degree of this contrast is shown to depend on water vapor-and cloud-radiative feedbacks that alter the effective strength of prescribed thermal forcing.open0

Sensitivity of Climate Change Induced by the Weakening of the Atlantic Meridional Overturning Circulation to Cloud Feedback

A variety of observational and modeling studies show that changes in the Atlantic meridional overturning circulation (AMOC) can induce rapid global-scale climate change. In particular, a substantially weakened AMOC leads to a southward shift of the intertropical convergence zone (ITCZ) in both the Atlantic and the Pacific Oceans. However, the simulated amplitudes of the AMOC-induced tropical climate change differ substantially among different models. In this paper, the sensitivity to cloud feedback of the climate response to a change in the AMOC is studied using a coupled ocean-atmosphere model [the GFDL Coupled Model, version 2.1 (CM2.1)]. Without cloud feedback, the simulated AMOC-induced climate change in this model is weakened substantially. Low-cloud feedback has a strong amplifying impact on the tropical ITCZ shift in this model, whereas the effects of high-cloud feedback are weaker. It is concluded that cloud feedback is an important contributor to the uncertainty in the global response to AMOC changes.open9

The response of the ITCZ to extratropical thermal forcing: Idealized slab-ocean experiments with a GCM

Using a comprehensive atmospheric GCM coupled to a slab mixed layer ocean, experiments are performed to study the mechanism by which displacements of the intertropical convergence zone (ITCZ) are forced from the extratropics. The northern extratropics are cooled and the southern extratropics are warmed by an imposed cross-equatorial flux beneath the mixed layer, forcing a southward shift in the ITCZ. The ITCZ displacement can be understood in terms of the degree of compensation between the imposed oceanic flux and the resulting response in the atmospheric energy transport in the tropics. The magnitude of the ITCZ displacement is very sensitive to a parameter in the convection scheme that limits the entrainment into convective plumes. The change in the convection scheme affects the extratropical-tropical interactions in the model primarily by modifying the cloud response. The results raise the possibility that the response of tropical precipitation to extratropical thermal forcing, important for a variety of problems in climate dynamics (such as the response of the tropics to the Northern Hemisphere ice sheets during glacial maxima or to variations in the Atlantic meridional overturning circulation), may be strongly dependent on cloud feedback. The model configuration described here is suggested as a useful benchmark helping to quantify extratropical-tropical interactions in atmospheric models.open988

Gpr37l1 Modulates Seizure Susceptibility: Evidence from Mouse Studies and Analyses of a Human Gpr37l1 Variant

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G \u3e T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy

Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype

Background A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals. Case presentation In this study, a 4-year-old patient with a severe phenotype of osteoporosis, hypotonia, joint laxity, fractures, scoliosis, biscuspid aortic valve and myopia was referred for next generation sequencing after extensive negative clinical testing. Whole exome sequencing was performed on the proband and his unaffected parents to identify the molecular basis of his disease. Sequencing revealed compound heterozygous variants in B3GAT3: c.1A > G (p.Met1?) and c.671 T > A (p.L224Q). Clinical and in vitro functional studies were then completed to verify the pathogenicity of the genotype and further characterize the functional basis of the patient’s disease demonstrating the patient had a decrease both in the protein level of B3GAT3 and in the glucuronyltransferase activity when compared to control samples. Independent in vitro assessment of each variant confirmed the B3GAT3: c.1A > G (p.Met1?) variant is functionally null and the c.671 T > A (p.L224Q) missense variant has significantly reduced glucuronyltransferase activity (~3% of control). Conclusions This is the first report of a patient with compound heterozygosity for a null variant in trans with a missense in B3GAT3 resulting in a severe phenotype, expanding both the genotypic and phenotypic spectrum of B3GAT3-related disease

Simulated Atmospheric N Deposition Alters Fungal Community Composition and Suppresses Ligninolytic Gene Expression in a Northern Hardwood Forest

High levels of atmospheric nitrogen (N) deposition may result in greater terrestrial carbon (C) storage. In a northern hardwood ecosystem, exposure to over a decade of simulated N deposition increased C storage in soil by slowing litter decay rates, rather than increasing detrital inputs. To understand the mechanisms underlying this response, we focused on the saprotrophic fungal community residing in the forest floor and employed molecular genetic approaches to determine if the slower decomposition rates resulted from down-regulation of the transcription of key lignocellulolytic genes, by a change in fungal community composition, or by a combination of the two mechanisms. Our results indicate that across four Acer-dominated forest stands spanning a 500-km transect, community-scale expression of the cellulolytic gene cbhI under elevated N deposition did not differ significantly from that under ambient levels of N deposition. In contrast, expression of the ligninolytic gene lcc was significantly down-regulated by a factor of 2–4 fold relative to its expression under ambient N deposition. Fungal community composition was examined at the most southerly of the four sites, in which consistently lower levels of cbhI and lcc gene expression were observed over a two-year period. We recovered 19 basidiomycete and 28 ascomycete rDNA 28S operational taxonomic units; Athelia, Sistotrema, Ceratobasidium and Ceratosebacina taxa dominated the basidiomycete assemblage, and Leotiomycetes dominated the ascomycetes. Simulated N deposition increased the proportion of basidiomycete sequences recovered from forest floor, whereas the proportion of ascomycetes in the community was significantly lower under elevated N deposition. Our results suggest that chronic atmospheric N deposition may lower decomposition rates through a combination of reduced expression of ligninolytic genes such as lcc, and compositional changes in the fungal community

Etiological distinction of working memory components in relation to mathematics.

Working memory has been consistently associated with mathematics achievement, although the etiology of these relations remains poorly understood. The present study examined the genetic and environmental underpinnings of math story problem solving, timed calculation, and untimed calculation alongside working memory components in 12-year-old monozygotic (n = 105) and same-sex dizygotic (n = 143) twin pairs. Results indicated significant phenotypic correlation between each working memory component and all mathematics outcomes (r = 0.18 - 0.33). Additive genetic influences shared between the visuo-spatial sketchpad and mathematics achievement was significant, accounting for roughly 89% of the observed correlation. In addition, genetic covariance was found between the phonological loop and math story problem solving. In contrast, despite there being a significant observed relationship between phonological loop and timed and untimed calculation, there was no significant genetic or environmental covariance between the phonological loop and timed or untimed calculation skills. Further analyses indicated that genetic overlap between the visuo-spatial sketchpad and math story problem solving and math fluency was distinct from general genetic factors, whereas g, phonological loop, and mathematics shared generalist genes. Thus, although each working memory component was related to mathematics, the etiology of their relationships may be distinct