A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome

Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel–Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VCRL1, adding a novel functionally tested disease allele. We also describe the first patient with NAD+ deficiency disorder resulting from a UPD. Furthermore, we provide a comprehensive review of the current literature covering the genetic basis and pathomechanisms for VCRL and Catel–Manzke Syndrome, including possible phenotype/genotype correlations as well as genetic causes of hypoplastic left heart syndrome

Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future

Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas

Background: Synovial sarcoma (SS) is a malignant soft tissue tumor of mesenchymal origin that frequently occurs in young adults. Translocation of the SYT gene on chromosome 18 to the SSX genes on chromosome X leads to the formation of oncogenic fusion genes, which lead to initiation and proliferation of tumor cells. The detection and quantification of circulating tumor DNA (ctDNA) can serve as a non-invasive method for diagnostics of local or distant tumor recurrence, which could improve survival rates due to early detection. Methods: We developed a subtype-specific targeted next-generation sequencing (NGS) approach specifically targeting SS t(X;18)(p11;q11), which fuses SS18 (SYT) in chromosome 18 to SSX1 or SSX2 in chromosome x, and recurrent point mutations. In addition, patient-specific panels were designed from tumor exome sequencing. Both approaches were used to quantify ctDNA in patients’ plasma. Results: The subtype-specific assay allowed detection of somatic mutations from 25/25 tumors with a mean of 1.68 targetable mutations. The minimal limit of detection was determined at a variant allele frequency of 0.05%. Analysis of 29 plasma samples from 15 tumor patients identified breakpoint ctDNA in 6 patients (sensitivity: 40%, specificity 100%). The addition of more mutations further increased assay sensitivity. Quantification of ctDNA in plasma samples (n = 11) from one patient collected over 3 years, with a patient-specific panel based on tumor exome sequencing, correlated with the clinical course, response to treatment and tumor volume. Conclusions: Targeted NGS allows for highly sensitive tumor profiling and non-invasive detection of ctDNA in SS patients, enabling non-invasive monitoring of tumor dynamics

Linking Remote Sensing and Geodiversity and Their Traits Relevant to Biodiversity—Part I: Soil Characteristics

In the face of rapid global change it is imperative to preserve geodiversity for the overallconservation of biodiversity. Geodiversity is important for understanding complex biogeochemicaland physical processes and is directly and indirectly linked to biodiversity on all scales of ecosystemorganization. Despite the great importance of geodiversity, there is a lack of suitable monitoringmethods. Compared to conventional in-situ techniques, remote sensing (RS) techniques providea pathway towards cost-effective, increasingly more available, comprehensive, and repeatable, aswell as standardized monitoring of continuous geodiversity on the local to global scale. This papergives an overview of the state-of-the-art approaches for monitoring soil characteristics and soilmoisture with unmanned aerial vehicles (UAV) and air- and spaceborne remote sensing techniques.Initially, the definitions for geodiversity along with its five essential characteristics are provided,with an explanation for the latter. Then, the approaches of spectral traits (ST) and spectral traitvariations (STV) to record geodiversity using RS are defined. LiDAR (light detection and ranging),thermal and microwave sensors, multispectral, and hyperspectral RS technologies to monitor soilcharacteristics and soil moisture are also presented. Furthermore, the paper discusses current andfuture satellite-borne sensors and missions as well as existing data products. Due to the prospectsand limitations of the characteristics of different RS sensors, only specific geotraits and geodiversitycharacteristics can be recorded. The paper provides an overview of those geotraits.Peer Reviewe

Linking Remote Sensing and Geodiversity and Their Traits Relevant to Biodiversity—Part I: Soil Characteristics

In the face of rapid global change it is imperative to preserve geodiversity for the overall conservation of biodiversity. Geodiversity is important for understanding complex biogeochemical and physical processes and is directly and indirectly linked to biodiversity on all scales of ecosystem organization. Despite the great importance of geodiversity, there is a lack of suitable monitoring methods. Compared to conventional in-situ techniques, remote sensing (RS) techniques provide a pathway towards cost-effective, increasingly more available, comprehensive, and repeatable, as well as standardized monitoring of continuous geodiversity on the local to global scale. This paper gives an overview of the state-of-the-art approaches for monitoring soil characteristics and soil moisture with unmanned aerial vehicles (UAV) and air- and spaceborne remote sensing techniques. Initially, the definitions for geodiversity along with its five essential characteristics are provided, with an explanation for the latter. Then, the approaches of spectral traits (ST) and spectral trait variations (STV) to record geodiversity using RS are defined. LiDAR (light detection and ranging), thermal and microwave sensors, multispectral, and hyperspectral RS technologies to monitor soil characteristics and soil moisture are also presented. Furthermore, the paper discusses current and future satellite-borne sensors and missions as well as existing data products. Due to the prospects and limitations of the characteristics of different RS sensors, only specific geotraits and geodiversity characteristics can be recorded. The paper provides an overview of those geotrait

Linking the Remote Sensing of Geodiversity and Traits Relevant to Biodiversity Part II: Geomorphology, Terrain and Surfaces

The status, changes, and disturbances in geomorphological regimes can be regarded as controlling and regulating factors for biodiversity. Therefore, monitoring geomorphology at local, regional, and global scales is not only necessary to conserve geodiversity, but also to preserve biodiversity, as well as to improve biodiversity conservation and ecosystem management. Numerous remote sensing (RS) approaches and platforms have been used in the past to enable a cost-effective, increasingly freely available, comprehensive, repetitive, standardized, and objective monitoring of geomorphological characteristics and their traits. This contribution provides a state-of-the-art review for the RS-based monitoring of these characteristics and traits, by presenting examples of aeolian, fluvial, and coastal landforms. Different examples for monitoring geomorphology as a crucial discipline of geodiversity using RS are provided, discussing the implementation of RS technologies such as LiDAR, RADAR, as well as multi-spectral and hyperspectral sensor technologies. Furthermore, data products and RS technologies that could be used in the future for monitoring geomorphology are introduced. The use of spectral traits (ST) and spectral trait variation (STV) approaches with RS enable the status, changes, and disturbances of geomorphic diversity to be monitored. We focus on the requirements for future geomorphology monitoring specifically aimed at overcoming some key limitations of ecological modeling, namely: the implementation and linking of in-situ, close-range, air- and spaceborne RS technologies, geomorphic traits, and data science approaches as crucial components for a better understanding of the geomorphic impacts on complex ecosystems. This paper aims to impart multidimensional geomorphic information obtained by RS for improved utilization in biodiversity monitorin

Chondrodysplasia and Abnormal Joint Development Associated with Mutations in IMPAD1, Encoding the Golgi-Resident Nucleotide Phosphatase, gPAPP

We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints