Genotype and Phenotype in 12 additional individuals with SATB2-Associated Syndrome

SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible

Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.

BACKGROUND:ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. RESULTS: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The epi-ADNP-1 episignature included ~ 6000 mostly hypomethylated CpGs, and the epi-ADNP-2 episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. CONCLUSIONS: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome

A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24

Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a ∼0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and β-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discusse

The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function

The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus

Brachydactyly

Brachydactyly ("short digits") is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. The various types of isolated brachydactyly are rare, except for types A3 and D. Brachydactyly can occur either as an isolated malformation or as a part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism

Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher’s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition

Do Farmers Manage weeds on Owned and Rented Land Differently? Evidence from U.S. Corn and Soybean Farms

BACKGROUND It has been frequently argued that growers have less incentive to manage the evolution and spread of herbicide‐resistant weeds on leased than on owned land. This is because resistance management provides long‐term rather than short‐term benefits that operators may be less assured of capturing on land they do not own. Yet, empirical evidence supporting this argument has been lacking. RESULTS This study reports on results from a large‐scale national survey of weed management and other crop production practices on US agricultural fields. Up to 11 weed management practices were compared across owner‐operated versus renter‐operated fields. Analysis of survey data from corn and soybean fields did not support the hypothesis that adoption of resistance management practices is lower on rented acres. In most instances, there were no statistically significant differences in herbicide use or weed management practices on rented versus owned land. This was true at both national and regional levels of analysis. Where there were significant differences, practices associated with greater herbicide resistance management were, as often as not, more prevalent on rented than owned land. CONCLUSIONS A useful area of future research would be to test for land tenure differences in resistance management using multivariate analysis to control for confounding effects. Unobserved farmer or land characteristics may be confounding results and masking land tenure effects. Results here, however, suggest that these other effects are dominating any obvious disincentive effects of land leasing on resistance management. Of greater concern, the adoption of key resistance management practices was low on both owned and rented land. © 2020 Society of Chemical Industr

Weed Control and Corn (Zea mays) Response to Planting Pattern and Herbicide Program with High Seeding Rates in North Carolina

Effective weed control in corn (Zea mays L.) is important to optimize yield. Concern over environmental impact of atrazine and selection for glyphosate resistance has increased the need to develop alternative strategies that use herbicides other than atrazine and glyphosate and appropriate cultural practices to control weeds. Research was conducted during 2011 and 2012 to determine weed and corn response to herbicide programs containing dicamba, glufosinate, and glyphosate applied postemergence alone or with atrazine in single- and twin-row planting patterns. Planting pattern had no effect on common ragweed (Ambrosia artemisiifolia L.) and Texas panicum (Panicum texanum L.) population and did not interact with herbicide program. Effective weed control hastened maturity in some but not all instances. Under weed-free conditions, corn grain yield was higher in 5 of 7 trials when planted in twin rows versus single rows at equivalent corn populations (141,000 plants ha−1). These results suggest that while planting pattern may not impact weed control dramatically, planting corn in twin rows may be an effective alternative to single-row planting patterns because of increased yield under high corn populations

Economic and Behavioral Drivers of Herbicide Resistance Management in the U.S.

Weeds invade farms, grow and reproduce aggressively. For more than half a century, the primary tool used by farmers to control weeds has been herbicides, but the effectiveness of herbicides is declining due to herbicide resistance. An option available for farmers to better balance weed control and herbicide resistance is to adopt resistance management practices. However, the adoption of resistance management has been low. This study aims to explore the impact of economic and behavioral factors on a farmer’s choice over chemical, cultural and mechanical tactics of weed control. I use multivariate regression analysis and a unique U.S. farm-level weed management data to identify the farmer and farm operation characteristics that are most associated with farmers’ weed management decisions. The analysis shows that the negative externality from weed mobility leads to a farmer’s more diligent weed and resistance management, while low risk tolerance and impatience discourage the adoption herbicide resistance management. The analysis also provides novel insights into how the economic and non-monetary motivations of farmers mutually relate to their use of alternative weed management practices