Delineation of the clinical phenotype associated with non-mosaic type-2 NF1 deletions: two case reports

Introduction Large deletions of the NF1 gene and its flanking regions are frequently associated with a severe clinical manifestation. Different types of gross NF1 deletion have been identified that are distinguishable both by their size and the number of genes included within the deleted regions. Type-1 NF1 deletions encompass 1.4 Mb and include 14 genes, whereas the much less common type-2 NF1 deletions span 1.2 Mb and contain 13 genes. Genotype-phenotype correlations in patients with large NF1 deletions are likely to be influenced by the nature and number of the genes deleted in addition to the NF1 gene. Whereas the clinical phenotype associated with type-1 NF1 deletions has been well documented, the detailed clinical characterization of patients with non-mosaic type-2 NF1 deletions has not so far been reported. Case presentation In the present report we characterized two Caucasian European patients with non-mosaic (germline) type-2 NF1 deletions. Our first patient was a 13-year-old girl with dysmorphic facial features, mild developmental delay, large hands and feet, hyperflexibility of the joints, macrocephaly and T2 hyperintensities in the brain. A whole-body magnetic resonance imaging scan indicated two internal plexiform neurofibromas. Our second patient was an 18-year-old man who exhibited dysmorphic facial features, developmental delay, learning disability, large hands and feet, hyperflexibility of the joints, macrocephaly and a very high subcutaneous and internal tumor load as measured volumetrically on whole-body magnetic resonance imaging scans. At the age of 18 years, he developed a malignant peripheral nerve sheath tumor and died from secondary complications. Both our patients exhibited cardiovascular malformations. Conclusions Our two patients with non-mosaic type-2 NF1 deletions exhibited clinical features that have been reported in individuals with germline type-1 NF1 deletions. Therefore, a severe disease manifestation is not confined to only patients with type-1 NF1 deletions but may also occur in individuals with type-2 NF1 deletions. Our findings support the concept of an NF1 microdeletion syndrome with severe clinical manifestation that is caused by type-1 as well as type-2 NF1 deletions

Evolutionary Breakpoints in the Gibbon Suggest Association between Cytosine Methylation and Karyotype Evolution

Gibbon species have accumulated an unusually high number of chromosomal changes since diverging from the common hominoid ancestor 15–18 million years ago. The cause of this increased rate of chromosomal rearrangements is not known, nor is it known if genome architecture has a role. To address this question, we analyzed sequences spanning 57 breaks of synteny between northern white-cheeked gibbons (Nomascus l. leucogenys) and humans. We find that the breakpoint regions are enriched in segmental duplications and repeats, with Alu elements being the most abundant. Alus located near the gibbon breakpoints (<150 bp) have a higher CpG content than other Alus. Bisulphite allelic sequencing reveals that these gibbon Alus have a lower average density of methylated cytosine that their human orthologues. The finding of higher CpG content and lower average CpG methylation suggests that the gibbon Alu elements are epigenetically distinct from their human orthologues. The association between undermethylation and chromosomal rearrangement in gibbons suggests a correlation between epigenetic state and structural genome variation in evolution

Towards a Reliable and Rapid Automated Grading System in Facial Palsy Patients: Facial Palsy Surgery Meets Computer Science

Background: Reliable, time- and cost-effective, and clinician-friendly diagnostic tools are cornerstones in facial palsy (FP) patient management. Different automated FP grading systems have been developed but revealed persisting downsides such as insufficient accuracy and cost-intensive hardware. We aimed to overcome these barriers and programmed an automated grading system for FP patients utilizing the House and Brackmann scale (HBS). Methods: Image datasets of 86 patients seen at the Department of Plastic, Hand, and Reconstructive Surgery at the University Hospital Regensburg, Germany, between June 2017 and May 2021, were used to train the neural network and evaluate its accuracy. Nine facial poses per patient were analyzed by the algorithm. Results: The algorithm showed an accuracy of 100%. Oversampling did not result in altered outcomes, while the direct form displayed superior accuracy levels when compared to the modular classification form (n = 86; 100% vs. 99%). The Early Fusion technique was linked to improved accuracy outcomes in comparison to the Late Fusion and sequential method (n = 86; 100% vs. 96% vs. 97%). Conclusions: Our automated FP grading system combines high-level accuracy with cost- and time-effectiveness. Our algorithm may accelerate the grading process in FP patients and facilitate the FP surgeon’s workflow

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A Ready-to-Use Grading Tool for Facial Palsy Examiners—Automated Grading System in Facial Palsy Patients Made Easy

Background: The grading process in facial palsy (FP) patients is crucial for time- and cost-effective therapy decision-making. The House-Brackmann scale (HBS) represents the most commonly used classification system in FP diagnostics. This study investigated the benefits of linking machine learning (ML) techniques with the HBS. Methods: Image datasets of 51 patients seen at the Department of Plastic, Hand, and Reconstructive Surgery at the University Hospital Regensburg, Germany, between June 2020 and May 2021, were used to build the neural network. A total of nine facial poses per patient were used to automatically determine the HBS. Results: The algorithm had an accuracy of 98%. The algorithm processed the real patient image series (i.e., nine images per patient) in 112 ms. For optimized accuracy, we found 30 training runs to be the most effective training length. Conclusion: We have developed an easy-to-use, time- and cost-efficient algorithm that provides highly accurate automated grading of FP patient images. In combination with our application, the algorithm may facilitate the FP surgeon’s clinical workflow

Comparing chromosomal and mitochondrial phylogenies of the Indriidae (Primates, Lemuriformes)

The Malagasy primate family Indriidae comprises three genera with up to 19 species. Cytogenetic and molecular phylogenies of the Indriidae have been performed with special attention to the genus Propithecus. Comparative R-banding and FISH with human paints were applied to karyotypes of representatives of all three genera and confirmed most of the earlier R-banding results. However, additional chromosomal rearrangements were detected. A reticulated and a cladistic phylogeny, the latter including hemiplasies, have been performed. Cladistic analysis of cytogenetic data resulted in a phylogenetic tree revealing (1) monophyly of the family Indriidae, (2) monophyly of the genus Avahi, (3) sister–group relationships between Propithecus diadema and Propithecus edwardsi, and (4) the grouping of the latter with Indri indri, Propithecus verreauxi, and Propithecus tattersalli, and thus suggesting paraphyly of the genus Propithecus. A molecular phylogeny based on complete mitochondrial cytochrome b sequences of 16 species indicated some identical relationships, such as the monophyly of Avahi and the sister–group relationships of the eastern (P. diadema and P. edwardsi) to the western Propithecus species (P. verreauxi, Propithecus coquereli, and P. tattersalli). However, the main difference between the molecular and cytogenetic phylogenies consists in an early divergence of Indri in the molecular phylogeny while in the chromosomal phylogeny it is nested within Propithecus. The similarities and differences between molecular and cytogenetic phylogenies in relation to data on the species’ geographic distributions and mating systems allow us to propose a scenario of the evolution of Indriidae. Chromosomal and molecular processes alone or in combination created a reproductive barrier that was then followed by further speciation processes

Upstream Solutions: Does the Supplemental Security Income Program Reduce Disability in the Elderly?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72843/1/j.1468-0009.2007.00512.x.pd

Evolution of a Bitter Taste Receptor Gene Cluster in a New World Sparrow

Bitter taste perception likely evolved as a protective mechanism against the ingestion of harmful compounds in food. The evolution of the taste receptor type 2 (TAS2R) gene family, which encodes the chemoreceptors that are directly responsible for the detection of bitter compounds, has therefore been of considerable interest. Though TAS2R repertoires have been characterized for a number of species, to date the complement of TAS2Rs from just one bird, the chicken, which had a notably small number of TAS2Rs, has been established. Here, we used targeted mapping and genomic sequencing in the white-throated sparrow (Zonotrichia albicollis) and sample sequencing in other closely related birds to reconstruct the history of a TAS2R gene cluster physically linked to the break points of an evolutionary chromosomal rearrangement. In the white-throated sparrow, this TAS2R cluster encodes up to 18 functional bitter taste receptors and likely underwent a large expansion that predates and/or coincides with the radiation of the Emberizinae subfamily into the New World. In addition to signatures of gene birth-and-death evolution within this cluster, estimates of Ka/Ks for the songbird TAS2Rs were similar to those previously observed in mammals, including humans. Finally, comparison of the complete genomic sequence of the cluster from two common haplotypes in the white-throated sparrow revealed a number of nonsynonymous variants and differences in functional gene content within this species. These results suggest that interspecies and intraspecies genetic variability does exist in avian TAS2Rs and that these differences could contribute to variation in bitter taste perception in birds