The genetic landscape of neurodevelopmental disorders is constantly expanding and children with early-onset neurological phenotypes increasingly receive a genetic diagnosis. Nonetheless, the ...awareness of the chronic course of these conditions, and consequently their recognition and management in the adult population, is still limited.
Herein, we describe four patients with rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1-related diseases), who received a genetic assignment only in the adulthood. All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood, prompting the referral to a neurologist. This phenotypic combination led eventually to the genetic testing. We report previously unrecognized features and highlight the peculiarities of the adult presentation of four neurodevelopmental disorders.
This report expands the current knowledge on four rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1), which was mainly based on reports from paediatric cases. This case series emphasize the importance of a tight neurological surveillance extending beyond the childhood.
The compound‐specific hydrogen isotopic composition (δ2H) of n‐alkanes is a valuable proxy to investigate hydrological conditions in lake sediments. While terrestrial n‐alkanes reflect the isotopic ...signal of the local precipitation, aquatic n‐alkanes incorporate the isotopic signal of the lake's water, which can be strongly modulated by evaporative enrichment. So far, the spatial distribution of the terrestrial and aquatic δ2H signal within lakes have not systematically been investigated. Here, we present compound‐specific δ2H results of terrestrial (δ2HC31) and aquatic (δ2HC23) n‐alkanes of surface sediment samples from Lake Khar Nuur, a semi‐arid and high‐altitude lake in the Mongolian Altai, and additionally investigate the δ2H signal of topsoils from the catchment. Our results show that the majority of the n‐alkane δ2H values from the catchment topsoils correspond well with modeled local growing season precipitation (JJAS). However, few samples in the northern catchment show more positive δ2H values possibly due to increased evapo(transpi)ration by southward exposition and shallower soils there. The only small variability of δ2HC31 in the surface sediments is in the range of most topsoils δ2H from the catchment, and thus, well reflects local growing season precipitation. δ2HC23 in surface sediment samples from the central and deepest parts of the lake, that is, the lake's sediment accumulation zones, shows distinctly more positive δ2HC23 values due to evaporative lake water enrichment. Consequently, Δaq‐terr, which is the isotopic offset between δ2HC23 and δ2HC31, indicates distinct lake water enrichment in the lake's accumulation zones and is a valuable proxy to investigate past hydrological changes.
Key Points
The hydrogen isotopic composition of terrestrial C31 n‐alkanes reflects the local growing season precipitation at Lake Khar Nuur
Aquatic C23 n‐alkanes incorporate the isotopic signal of the lake's water, which is strongly modulated by evaporative enrichment
The isotopic offset between C23 and C31 is a valuable proxy for evaporation in the lake and past hydrological changes in the catchment
Loess in the Carpathian Basin is some of the thickest and most complete in Europe. Located in the Vojvodina region of the southern Carpathian Basin the Crvenka loess-palaeosol section appears to ...preserve a detailed climate proxy archive of the last glacial–interglacial cycle. Central to the interpretation of the site is a detailed and independent age model. Here, the results of detailed optically stimulated luminescence (OSL) dating and elevated temperature post-IR infrared stimulated luminescence (post-IR IRSL) dating are presented. Quartz OSL ages appear accurate to about 50–60 ka, where 2D
0 values are reached, while elevated temperature post-IR IRSL yields more accurate ages below this. In line with recent results, the latter signal appears to show negligible fading rates. Two age models are developed that combine (a) OSL and post-IR IRSL ages and (b) OSL ages and ‘expected’ ages from tying unit boundaries to the marine record. If the luminescence model is regarded as accurate, differences between this and the OSL/marine age model raise questions over the accuracy of the latter, as well as the processes controlling the zeroing of luminescence dates. The luminescence based age model is then used to derive the first fully independent reconstruction of climate proxies and accumulation rates from Carpathian loess. Such reconstructions can be used to compare to other independent records without assumptions inherent in correlation-based approaches. The findings demonstrate how variable accumulation rate is at the site, and compared to other independently dated Carpathian loess records. Average values vary north–south but are of similar order throughout the basin. Accumulation rate was highest during the later part of the last glacial, but variation on millennial timescales does not always match shifts in grain-size, suggesting diverse and complex influences. Environmental reconstructions using grain-size and magnetic susceptibility show that no one atmospheric system or air mass can explain the changes in the Carpathian Basin and that millennial-scale variability can only intermittently be tied to North Atlantic Heinrich events. Expanded ice sheets during the peak last glacial, combined with other atmospheric teleconnections, may have served to develop a strong anticyclone in the region. It was likely windier during earlier parts of the last glacial, but Atlantic and Mediterranean moisture was probably less abundant than during more humid interglacials.
The Danube River drainage basin is the second largest river catchment in Europe and contains a significant and extensive region of thick loess deposits that preserve a record of a wide variety of ...recent and past environments. Indeed, the Danube River and tributaries may themselves be responsible for the transportation of large volumes of silt that ultimately drive loess formation in the middle and lower reaches of this large catchment. However, this vast loess province lacks a unified stratigraphic scheme. European loess research started in the late 17th century in the Danube Basin with the work of Count Luigi Ferdinand Marsigli. Since that time numerous investigations provided the basis for the pioneering stratigraphic framework proposed initially by Kukla (1970, 1977) in his correlations of loess with deep-sea sediments. Loess–palaeosol sequences in the middle and lower reaches of the Danube River basin were a key part of this framework and contain some of the longest and most complete continental climate records in Europe, covering more than the last million years. However, the very size of the Danube loess belt and the large number of countries it covers presents a major limiting factor in developing a unified approach that enables continental scale analysis of the deposits. Local loess–palaeosol stratigraphic schemes have been defined separately in different countries and the difficulties in correlating such schemes, which often change significantly with advances in age-dating, have limited the number of basin-wide studies. A unified basin-wide stratigraphic model would greatly alleviate these difficulties and facilitate research into the wider significance of these loess records. Therefore we review the existing stratigraphic schemes and define a new Danube Basin wide loess stratigraphy based around a synthetic type section of the Mošorin and Stari Slankamen sites in Serbia. We present a detailed comparison with the sedimentological and palaeoclimatic records preserved in sediments of the Chinese Loess Plateau, with the oxygen isotope records from deep-sea sediments, and with classic European Pleistocene stratigraphic subdivisions. The hierarchy of Danubian stratigraphic units is determined by climatically controlled environmental shifts, in a similar way to the Chinese loess stratigraphic scheme. A new unified Danube loess stratigraphic model has a number of advantages, including preventing confusion resulting from the use of multiple national schemes, a more transparent basis, and the potential to set Pleistocene palaeoenvironmental changes recorded in the Danube catchment area into a global context. The use of a very simple labelling system based on the well-established Chinese loess scheme facilitates interpretation of palaeoenvironmental information reported from the Danube Basin loess sites in a wider more accessible context that can be readily correlated world-wide. This stratigraphic approach also provides, for the first time, an appropriate framework for the development of an integrated, pan-European and potentially pan-Eurasian loess stratigraphic scheme.
Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene ...trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs∗17), in KMT2B, encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B—one de novo nonsense mutation (c.1633C>T p.Arg545∗), one de novo essential splice-site mutation (c.7050−2A>G p.Phe2321Serfs∗93), and one inherited nonsense mutation (c.2428C>T p.Gln810∗) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C>T (p.Gln810∗) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B. Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis.
Abstract
Isotope-based records provide valuable information on past climate changes. However, it is not always trivial to disentangle past changes in the isotopic composition of precipitation from ...possible changes in evaporative enrichment, and seasonality may need to be considered. Here, we analyzed δ
2
H on
n
-alkanes and δ
18
O on hemicellulose sugars in sediments from Bichlersee, Bavaria, covering the Late Glacial and Early Holocene. Our δ
2
H
n
-C31
record documents past changes in the isotopic composition of summer precipitation and roughly shows the isotope pattern known from Greenland. Both records show lower values during the Younger Dryas, but at Bichlersee the signal is less pronounced, corroborating earlier suggestions that the Younger Dryas was mainly a winter phenomenon and less extreme during summer. δ
18
O
fucose
records the isotopic composition of the lake water during summer and is sensitive to evaporative enrichment. Coupling δ
2
H
n
-C31
and δ
18
O
fucose
allows calculating lake water deuterium-excess and thus disentangling changes in the isotopic composition of precipitation and evaporative enrichment. Our deuterium-excess record reveals that the warm Bølling–Allerød and Early Holocene were characterized by more evaporative enrichment compared to the colder Younger Dryas. Site-specific hydrological conditions, seasonality, and coupling δ
2
H and δ
18
O are thus important when interpreting isotope records.
The repeated expansion of East Asian steppe cultures was a key driver of Eurasian history, forging new social, economic, and biological links across the continent. Climate has been suggested as ...important driver of these poorly understood cultural expansions, but paleoclimate records from the Mongolian Plateau often suffer from poor age control or ambiguous proxy interpretation. Here, we use a combination of geochemical analyses and comprehensive radiocarbon dating to establish the first robust and detailed record of paleohydrological conditions for Lake Telmen, Mongolia, covering the past ~ 4000 years. Our record shows that humid conditions coincided with solar minima, and hydrological modeling confirms the high sensitivity of the lake to paleoclimate changes. Careful comparisons with archaeological and historical records suggest that in the vast semi-arid grasslands of eastern Eurasia, solar minima led to reduced temperatures, less evaporation, and high biomass production, expanding the power base for pastoral economies and horse cavalry. Our findings suggest a crucial link between temperature dynamics in the Eastern Steppe and key social developments, such as the emergence of pastoral empires, and fuel concerns that global warming enhances water scarcity in the semi-arid regions of interior Eurasia.
Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying ...monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
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