My edit history statistics – includes my general editing statistics (e.g., monthly/yearly and cumulative edit counts), a list of pages I've edited the most, and a breakdown of my edits by namespace.
Some of my most notable contributions to Wikipedia:
Articles: This list includes articles in which I've written >80% of the source code (according to xTools' authorship attribution for the article) and for which I've spent the most time locating, reading, and citing WP:MEDRS-quality sources.
Lists: These pages contain a complete list of all known human protein-coding genes. I've been using a Python algorithm to regularly rewrite/update them.
Chinese-Wikipedia – zh:User:Seppi333 (I mainly assist with porting my contributions in articles/templates over to this Wikipedia; I can't read/write Chinese)
Quick summary of findings from a few of the teams:
Multiple teams implicated TTN in the pathophysiology of John's clinical phenotype (see here for a list of TTN mutations).
Two teams implicated TNXBhaploinsufficiency (technically, TNXB deficiency), manifesting as hypermobile Ehlers-Danlos syndrome, due to compound heterozygous frameshift mutations in this gene, both of which occur at tenascin-X glycine residue 362.
Several teams implicated genes associated with a congenital disorder of glycosylation; other genes related to lipid metabolism/storage, were also implicated in the etiology of his metabolic phenotype.
NB: I haven't yet looked into the genes implicated in the etiology of John's immunological phenotype, so I can't summarize this.
The following symptoms that John experiences are associated with TNXB loss of function mutations: NB: complete TNXB deficiency normally causes classic-like EDS and manifests with a much more pronounced phenotype than what John experiences; his clinical phenotype is much more similar to hypermobile EDS, most notably due to an apparently complete lack of skin involvement, so it would seem that John's genotype is not fully penetrant for clEDS.
elevated plasma histamine (likely reflects the involvement of mast cell disorders in EDS per [2])
Hackathon teams that identified the biallelic frameshift variants in his TNXB gene: Genobank & Tenacity (PPT) – both found it with Qiagen's proprietary Ingenuity Variant Analysis software.
Relevant studies
Collapsed since I was looking primarily for sources on TNXB haploinsufficiency at the time. Seppi333 (Insert 2¢) 14:43, 20 May 2020 (UTC)
PubMed search link for ("TNXB"[Title/abstract] OR "tenascin-X"[Title/abstract] OR "tenascin X"[Title/abstract]) AND ("EDS"[Title/abstract] OR "Ehlers-Danlos syndrome"[Title/abstract] OR "joint hypermobility"[Title/abstract])
Primary study (2003): Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome "Clinically, patients with reduced TNX levels showed hypermobile joints, often associated with joint subluxations and chronic musculoskeletal pain (table 1). The clinical findings in these patients differ from those with complete TNX deficiency. Patients with haploinsufficiency do not have skin hyperextensibility and lack the easy bruising seen in patients with TNX deficiency. In addition, TNXB haploinsufficiency is expected to be an autosomal dominant trait, which is in accordance with the observed mode of inheritance of HT-EDS and BJHS."
Primary study (2013): Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia (NB: the TNXB gene overlaps the CYP21A2 gene at its 3' ends; this paper is about mutations which affect both TNXB/CYP21A2, resulting in CAH & EDS) "Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. → high penetrance of haploinsufficiency
Primary study (2019): Measurement of Serum Tenascin-X in Joint Hypermobility Syndrome Patients "In conclusion, we found out that sTNX concentrations in half of the 17 JHS/hEDS patients were significantly lower than those in healthy individuals and there were no mutations, insertions or deletions in TNXB except for one patient. At present, the reason for reduction in sTNX concentration without mutations of TNXB is not clear, but the expression of TNX might be affected by epigenetic changes that occur in the JHS/hEDS patients. Therefore, the results indicate that measurement of the sTNX concentration in patients with JHS/hEDS is beneficial and the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS." – might be worth getting a TNXB ELISA if the antibody can actually bind to John’s mutant tenascin-X proteins, but altered protein function needs to be considered.
Review (2018): Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome. "Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a "contiguous gene syndrome" consisting of CAH and EDS. Heterozygosity for TNXB mutations causing haploinsufficiency of TNX may be associated with the mild "hypermobility form" of EDS, which principally affects small and large joints. Studies of patients with salt-wasting CAH found that up to 10% had clinical features of EDS, associated joint hypermobility, haploinsufficiency of TNX and heterozygosity for TNXB mutations, now called 'CAH-X.'"
Primary study (2016): Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia "Hypermobility type EDS is the mildest EDS subtype with generalized joint hypermobility, recurrent joint dislocations and chronic arthralgias can occur, and mild skin manifestations such as smooth, velvety skin may also be present. The genetic etiology of hypermobility type EDS is largely unknown (De Paepe and Malfait, 2012; Sobey, 2014). In this report, we describe a subtype of EDS in CAH patients with biallelic TNXB variants that clinically resembles the classical type EDS phenotype. Prior studies of patients with CAH and monoallelic TNXB variants reported a phenotype similar to the hypermobility type EDS (Merke, et al., 2013; Morissette, et al., 2015). ... This study describes a biallelic form of CAH-X syndrome that is clinically and biochemically more severe than the monoallelic forms previously described (Merke, et al., 2013; Morissette, et al., 2015). We have chosen to use the terminology “biallelic”, rather than “autosomal recessive” to describe our CAH patients with TNXB variants on both alleles because the term “autosomal recessive” by definition implies that having a deleterious variant on one allele does not result in a clinical phenotype. Clearly this is not the case with CAH-X. Similarly, biallelic variants of well-established autosomal dominant disorders resulting in a more severe phenotype have been described in polycystic kidney disease (Bergmann, et al., 2011; Hopp, et al., 2012; Sandford, 2009), familial hypercholesterolemia (Varret, et al., 2008) and inherited cancers (Rahman and Scott, 2007). Thus, our findings reflect complex genetic heterogeneity not unexpected. ... However, the development of in vitro constructs for probing variants in TNX and the effect on its mechanism of action would provide useful functional information."
Given what the Ehlers-Danlos society has written about the association between TNXB haploinsufficieny and hypermobile EDS as well as TNXB deficiency and classical-like EDS − and that John's clinical phenotype is more characteristic of hEDS diagnosis while his genotype is diagnostic for clEDS due to complete TNXB deficiency − this actually seems more of a research issue than a diagnostic one. Hence, have referred him to contact the EDS society directly for assistance with his case. Seppi333 (Insert 2¢) 03:27, 18 May 2020 (UTC)
Pending analysis (2nd) - pending admission, I'm just leaving this to the UDN; otherwise, I'll construct a customized GCP pipeline to do my own hybrid assembly, use a novel non-DeepVariant, AI-based variant caller, and then annotate the variants with both pre-existing software as well as my own NLP-based content similarity approach using an annotation database and the medical records textract files to do my own analysis. Then, will compare to Hackathon teams that focused their analysis on this subset of protein-coding genes.
inability to gain body fat or lean mass despite consuming sufficient calories (symptom is highly responsive to chronic benzodiazepine use, during which it largely resolves [i.e., results in a gain of ~10-20 pounds of body mass]; body weight eventually returns to an abnormally low baseline upon cessation of benzodiazepine use)
multiple abnormally high glycosylphosphatidylinositide (GPI-anchored) lipid biomarkers – metabolome profiling revealed over half a dozen GPI-anchored lipids with serum concentrations of ~3σs above their population means
... [incomplete list]
Clinical immunological phenotype
I don't have a working knowledge of immune defense against viral pathogens and only a basic understanding for fungal pathogens, so I haven't gone through these hackathon analyses.
Pending analysis (3rd) - pending admission, I'm just leaving this to the UDN; otherwise, I'll see if I can augment the analyses from the hackathon with a hybrid nanopore/Illumina assembly and apply the suggested types of variant callers mentioned in the presentations.
Four possible cases of stationarity and nonstationarity (with an I(1) unit root) for regressors and the error term (yt=α+βxt+μt). The time-series behavior of y is governed by the behavior of x and μ:
<ref name="NHMH_3e-#">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071827706 | edition = 3rd | chapter = Chapter #:XYZ | quote= }}</ref>
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter #:XYZ". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. XX–YY. ISBN9780071481274.
^Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter #:XYZ". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN9780071827706.
^Wooldridge, Jeffrey (2012). "Chapter #: XYZ". Introductory Econometrics: A Modern Approach (5th ed.). South-Western Cengage Learning. pp. XX–YY. ISBN9781111531041.
^Greene, William (2012). "Chapter #: XYZ". Econometric Analysis (7th ed.). Pearson Education. pp. XX–YY. ISBN9780273753568.
{{cns}} – Generates a CN tag with text span to highlight specific text that requires citations. Ex: {{cns|this text}} generates this text[citation needed]