Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes.

BACKGROUND: Significant human diseases/phenotypes exist which require both an environmental trigger event and a genetic predisposition before the disease/phenotype emerges, e.g. Carbamazepine with the rare SNP allele of rs3909184 causing Stevens Johnson syndrome, and aminoglycosides with rs267606617 causing sensory neural deafness. The underlying genotypes are fully penetrant only when the correct environmental trigger(s) occur, otherwise they are silent and harmless. Such diseases/phenotypes will not appear to have a Mendelian inheritance pattern, unless the environmental trigger is very common (>50% per lifetime). The known causative genotypes are likely to be protein-altering SNPs with dominant/semi-dominant effect. We questioned whether other diseases and phenotypes could have a similar aetiology. METHODS: We wrote the fSNPd program to analyse multiple exomes from a test cohort simultaneously with the purpose of identifying SNP alleles at a significantly different frequency to that of the general population. fSNPd was tested on trial cohorts, iteratively improved, and modelled for performance against an idealised association study under mutliple parameters. We also assessed the seqeuncing depath of all human exons to determine which were sufficiently well sequenced in an exome to be sued by fSNPd - by assessing forty exomes base by base. RESULTS: We describe a simple methodology for the detection of SNPs capable of causing a phenotype triggered by an environmental event. This uses cohorts of relatively small size (30-100 individuals) with the phenotype being investigated, their exomes, and thence seeks SNP allele frequencies significantly different from expected to identify potentially clinically important, protein altering SNP alleles. The strengths and weaknesses of this approach for discovering significant genetic causes of human disease are comparable to Mendelian disease mutation detection and Association Studies. CONCLUSIONS: The fSNPd methodology is another approach, and has potentially significant advantage over Association studies in needing far fewer individuals, to detect genes involved in the pathogenesis of a diseases/phenotypes. Furthermore, the SNP alleles identified alter amino acids, potentially making it easier to devise functional assays of protein function to determine pathogenicity

Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit.

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant KV6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express KV2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing KV6.4-Met419, the voltage dependence of inactivation for KV2.1 is more depolarized compared with neurons overexpressing KV6.4. Finally, KV6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that KV6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.MCL, DKM, DW, and CGW acknowledge funding from Addenbrooke’s Charitable Trust and the NIHR Cambridge Biomedical Research Centre. MN was funded by the Wellcome Trust (200183/Z/15/Z); JH and ESS by a Rosetrees Postdoctoral Grant (A1296) and the BBSRC (BB/R006210/1); GC and ESS by Versus Arthritis Grants (RG21973); VBL and FR by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and a joint MRC programme within the Metabolic Diseases Unit (MRC_MC_UU_12012/3). EF, GI and CB were funded by the Cambridge NIHR Biomedical Research Centre Integrative Genomics theme and LAP by a BBSRC-funded studentship (BB/M011194/1)

Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BackgroundComplex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition.MethodsExome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.ResultsIn the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls.ConclusionA single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1

M.O.M: My Own Map HMM Techniques for Predicting Wandering in Alzheimer’s and Dementia Patients

With the number of people suffering from Alzheimer’s Disease and Dementia expected to grow over the next couple decades, the need for assistive technologies to help promote their independent living is both imperative and imminent. Here, I focus specifically on the issue of wandering in these patients and propose the basis for a mobile application that could predict when they are wandering. I describe an approach to wandering prediction that involves the use of Hidden Markov Model (HMM) variants to encapsulate movement patterns and distinguish low probability movement sequences as wandering. Specifically, I consider a physics based HMM utilizing both speed and directional information to model movement and an HMM that models movement trajectories with smooth, polynomial curves. I describe the overall structure of these variants and evaluate their performance on both artificial GPS data logs as well as those taken from a real individual

The Role of Online Arts and Humanities in Medical Student Education: Mixed Methods Study of Feasibility and Perceived Impact of a 1-Week Online Course

BackgroundThe arts and humanities have been integrated into medical student education worldwide. Integrated arts and humanities courses have been found to serve four primary functions: mastering skills, perspective taking, personal insight, and social advocacy. To what extent and how arts and humanities programs achieve these educational outcomes remain unclear. ObjectiveIn this study, we aimed to explore how the arts and humanities may lead to perceived benefits in clinical skills development, professional identity formation, and self-care, and to evaluate the feasibility of delivering an arts and humanities–based course online. MethodsWe developed and delivered a 1-week online arts and humanities course to second- through fourth-year medical students. A total of 18 students enrolled in the course across its 2 offerings in Spring 2020. The course was primarily visual arts based but also included activities based in other arts and humanities, such as literature, reflective writing, dance, film, music, philosophy, and religion. Using a mixed methods approach, daily polls assessed student engagement in and perceptions of the various activities, and a postcourse survey assessed student perceptions of the course as a whole. ResultsAt least 93% of poll respondents (14/15 to 17/18) across the 2 cohorts rated each type of activity as good or excellent. Qualitative analysis of student responses to the postcourse survey revealed themes concerning both the form (overall course design and online format) and the function of the course (skills development, appreciation of new perspectives, and personal inquiry). ConclusionsResults suggested that the arts and humanities may support the development of clinically relevant skills and attitudes. A more unique finding was that integrative arts and humanities courses delivered online—including those that are primarily visual arts based—engage students and may yield personal and professional benefits

Additional file 1: of Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes

Use of fSNPd and the Supplementary Figure. This firstly documents the instructions for the installation of fSNPd, and its use. Secondly, it contains the Supplemental Figure entitled: Average read depth per base of genes in a test cohort of 40 individuals’ exomes - data derived from Supplemental Table S1. This shows a graph of calculate the average read coverage by all genes, and the legend details the methodology used. References used are given after the legend. Read number statistics of average depth of sequence reads for each exon of each gene included in the exomes of forty individuals. This is a large spreadsheet giving the detailed analysis of read depth achieved. Results and statistics are given for each gene and exon of each gene. Thus, the coverage of an exome of any desired exon can be determined. Simulations of the performance of fSNPd compared to an Association study approach in a variety of scenarios. Simulations were performed assuming that a rare SNP allele was fully penetrant when present (unless otherwise stated). For each Simulation SNP-1 is a common SNP (such as are used in Association studies) with allele A frequency = allele B frequency = 0.5 and SNP-2 (analysed in fSNPd) has the rare allele A frequency = .01 and the common allele B frequency = .99. The SNP-2 allele A is disease associated and always on a SNP-1 allele A background. Simulation are of: the number of SNPs causing a phenotype; different SNP-2 rare allele frequencies; if half of cases are non-genetic or rare SNPs allele penetrance 50%; and of using a cohort size of 3000, rather than 100 as used for all other simulations. (ZIP 8041 kb

Cross-modality mapping using image varifolds to align tissue-scale atlases to molecular-scale measures with application to 2D brain sections

International audienceThis paper explicates a solution to building correspondences between molecular-scale transcriptomics and tissue-scale atlases. This problem arises in atlas construction and cross-specimen/technology alignment where specimens per emerging technology remain sparse and conventional image representations cannot efficiently model the high dimensions from subcellular detection of thousands of genes. We address these challenges by representing spatial transcriptomics data as generalized functions encoding position and high-dimensional feature (gene, cell type) identity. We map onto low-dimensional atlas ontologies by modeling regions as homogeneous random fields with unknown transcriptomic feature distribution. We solve simultaneously for the minimizing geodesic diffeomorphism of coordinates through LDDMM and for these latent feature densities. We map tissue-scale mouse brain atlases to gene-based and cell-based transcriptomics data from MERFISH and BARseq technologies and to histopathology and cross-species atlases to illustrate integration of diverse molecular and cellular datasets into a single coordinate system as a means of comparison and further atlas construction

PEHO syndrome: the endpoint of different genetic epilepsies.

BACKGROUND: Progressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder. METHOD: Children with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra-interfamilial phenotypic correlations and genotype-phenotype correlations when pathological mutations were identified. RESULTS: Twenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl's DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes. CONCLUSIONS: We found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities-and are phenotypic endpoints of many severe genetic encephalopathies

Evidence of a genetic background predisposing to Complex Regional Pain Syndrome type 1

Background Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling, and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared to those who do not have the condition. Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a Discovery Cohort of well-characterised patients with chronic CRPS-1 (n=34) compared to population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a Replication Cohort (n=50). Gene expression of peripheral blood macrophages was assessed. Results In the Discovery Cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The Replication Cohort confirmed this finding. In a Chronic Pain Cohort these alleles were not overexpressed. In total 25/84 (29.8%) of patients with CRPS-1 expressed a rare allele. The SNPs were; rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1, and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8/14 (57.1%) versus 17/70 (24.3%), (Fischer’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. Conclusion A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1