10 research outputs found
Kant, race, and natural history
This article presents a new argument concerning the relation between Kant’s theory of race and aspects of the critical philosophy. It argues that Kant’s treatment of the problem of the systematic unity of nature and knowledge in the Critique of Pure Reason and the Critique of the Power of Judgment can be traced back a methodological problem in the natural history of the period – that of the possibility of a natural system of nature. Kant’s transformation of the methodological problem from natural history into a set of philosophical (and specifically epistemological) problems proceeds by way of the working out of his own problem in natural history – the problem of the natural history of the human races – and specifically the problem of the unity in diversity of the human species, in response to which he develops a theory of race. This theory of race is, further, the first developed model of the use of teleological judgment in Kant’s work. The article thus argues that Kant’s philosophical position on the systematic unity of nature and of knowledge in the first and third Critiques, and his account and defense of teleological judgment, are developed out of problems first articulated in his solution to the problem of the unity in diversity of the human species – that is, in his theory of race. The article does not seek to establish that these aspects of the critical philosophy are therefore racialised. But it does demonstrate, against those who deny its salience to his philosophy, how the problem of the unity in diversity of the human species and Kant’s theory of race is significant for the development of aspects of the critical philosophy and thus contributes to their philosophical problematics
An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.
Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations
An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome
Abstract
Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an “intermediate” DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations
A Large-Scale, Consortium-Based Genomewide Association Study of Asthma
BACKGROUND
Susceptibility to asthma is influenced by genes and environment;
implicated genes may indicate pathways for therapeutic intervention.
Genetic risk factors may be useful in identifying subtypes of asthma and
determining whether intermediate phenotypes, such as elevation of the
total serum IgE level, are causally linked to disease.
METHODS
We carried out a genomewide association study by genotyping 10,365
persons with physician-diagnosed asthma and 16,110 unaffected persons,
all of whom were matched for ancestry. We used random-effects pooled
analysis to test for association in the overall study population and in
subgroups of subjects with childhood-onset asthma (defined as asthma
developing before 16 years of age), later-onset asthma, severe asthma,
and occupational asthma.
RESULTS
We observed associations of genomewide significance between asthma and
the following single-nucleotide polymorphisms: rs3771166 on chromosome
2, implicating IL1RL1/IL18R1 (P = 3x10(-9)); rs9273349 on chromosome 6,
implicating HLA-DQ (P = 7x10(-14)); rs1342326 on chromosome 9, flanking
IL33 (P = 9x10(-10)); rs744910 on chromosome 15 in SMAD3 (P = 4x10(-9));
and rs2284033 on chromosome 22 in IL2RB (P = 1.1x10(-8)). Association
with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to
childhood-onset disease (rs2305480, P = 6x10(-23)). Only HLA-DR showed a
significant genomewide association with the total serum IgE
concentration, and loci strongly associated with IgE levels were not
associated with asthma.
CONCLUSIONS
Asthma is genetically heterogeneous. A few common alleles are associated
with disease risk at all ages. Implicated genes suggest a role for
communication of epithelial damage to the adaptive immune system and
activation of airway inflammation. Variants at the ORMDL3/GSDMB locus
are associated only with childhood-onset disease. Elevation of total
serum IgE levels has a minor role in the development of asthma