A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have ...not attempted to account for alterations in specific genes, and could not distinguish between nonsense mutations and loss of heterozygosity (LOH).
Here, we present a mechanistic approach to modelling initiation and malignant transformation in schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH.
This results in new estimates for the base-pair mutation rate u = 4.48 × 10
and the rate of LOH = 2.03 × 10
/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation.
We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.
A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but ...impact of combination with clinical and hormonal risk factors is unclear.
We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data.
Unadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes).
The combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.
Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous ...germline variants in
and
encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS.
We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had
pathogenic variants and 46 had no identified mutation.
Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in
were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic
variants (p=0.03). Patients with
pathogenic variants were significantly more likely than those with
pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004).
We propose that the clinical heterogeneity of GS can in part be explained by the underlying or
variant.
Recent genetic sequencing studies in large series’ of predominantly childhood medulloblastoma have implicated loss-of-function, predominantly truncating, variants in the
ELP1
and
GPR161
genes in ...causation of the MB
SHH
subtype specifically. The latter association, along with a report of an index case with some features of Gorlin syndrome has led to speculation that
GPR161
may also cause Gorlin syndrome. We show that these genes are associated with relatively low absolute risks of medulloblastoma from extrapolating lifetime risks in the general population and odds ratios from the population database gnomAD. The projected risks are around 1 in 270–430 for
ELP1
and 1 in 1600–2500 for
GPR161.
These risks do not suggest the need for MRI screening in infants with
ELP1
or
GPR161
variants as this is not currently recommended for
PTCH1
where the risks are equivalent or higher. We also screened 27
PTCH1/SUFU
pathogenic variant-negative patients with Gorlin syndrome for
GPR161
and found no suspicious variants. Given the population frequencies of 0.0962% for
GPR161
and 0.0687% for
ELP1
, neither of these genes can be a cause of Gorlin syndrome with an unexplained population frequency far lower at 0.0021%.
Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that ...cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non‐mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non‐NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non‐NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.
Here we introduce a Rapid Adaptable Portable In vitro Detection biosensor platform (RAPID) for detecting ligands that interact with nuclear hormone receptors (NHRs). The RAPID platform can be adapted ...for field use, allowing rapid evaluation of endocrine disrupting chemicals (EDCs) presence or absence in environmental samples, and can also be applied for drug screening. The biosensor is based on an engineered, allosterically activated fusion protein, which contains the ligand binding domain from a target NHR (human thyroid receptor β in this work). In vitro expression of this protein using cell-free protein synthesis (CFPS) technology in the presence of an EDC leads to activation of a reporter enzyme, reported through a straightforward colorimetric assay output. In this work, we demonstrate the potential of this biosensor platform to be used in a portable “just-add-sample” format for near real-time detection. We also demonstrate the robust nature of the cell-free protein synthesis component in the presence of a variety of environmental and human samples, including sewage, blood, and urine. The presented RAPID biosensor platform is significantly faster and less labor intensive than commonly available technologies, making it a promising tool for detecting environmental EDC contamination and screening potential NHR-targeted pharmaceuticals.
Objectives:
This study aims to investigate the impact of a therapeutic horse riding (HR) intervention and an audiovisual (AV) intervention comprising exposure to equine rhythm and motion on ...developmental parameters of children with Developmental Coordination Disorder (DCD).
Design:
The study design was a pretest/post-test.
Settings/Location:
The study took place in three locations across Ireland—St. Michael's Boys School in Mervue, Co Galway, The Hunt Museum in Limerick City, Co. Limerick, and Fettercairn Youth Horse Project in Tallaght, Co. Dublin.
Subjects:
Eighty-three children (6–14 years) with a primary diagnosis of DCD.
Interventions:
Children meeting the inclusion criteria were divided into three groups: HR, AV, and a control (C) group. Those in the intervention groups participated in eight 30 min HR lessons or AV screening sessions.
Outcome measures:
A Childhood Depression Inventory (CDI) measured signs of depression. A Childhood Behavior CheckList (CBCL) determined any behavioral and emotional problems, while a Social Responsiveness Scale (SRS) assessed the presence and extent of any social impairment. A GAITRite system provided an overall Functional Ambulation Performance (FAP) score (an automatic accumulated score of gait parameters, including gait speed, symmetry, distance, cadence, tension, support, and velocity), which was used to evaluate gait improvements.
Results:
Repeated measures analysis of variance revealed a main effect of time on all variables. Bonferroni
post hoc
tests revealed that these effects were due to significant improvements in both HR and AV groups for CDI, CBCL, and SRS, and significant improvements in the HR group only for FAP.
Conclusions:
This study provides initial evidence to support the value of an equine AV perception intervention at improving developmental parameters in children with DCD and provides additional support for the benefits of therapeutic HR on social, emotional, behavioral, and gait variables in these children.
Abstract
Background
Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design.
Methods
A prospective database of patients meeting NF2 diagnostic ...criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death.
Results
Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004).
Conclusion
Understanding disease course improves prognostication, allowing for better-informed decisions about care.
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