Abstract
Kawasaki disease (KD) is the most common acquired pediatric heart disease. We analyzed Whole Genome Sequences (WGS) from a 6-member African American family in which KD affected two of four children. We sought rare, potentially causative genotypes by sequentially applying the following WGS filters: sequence quality scores, inheritance model (recessive homozygous and compound heterozygous), predicted deleteriousness, allele frequency, genes in KD-associated pathways or with significant associations in published KD genome-wide association studies (GWAS), and with differential expression in KD blood transcriptomes. Biologically plausible genotypes were identified in twelve variants in six genes in the two affected children. The affected siblings were compound heterozygous for the rare variants p.Leu194Pro and p.Arg247Lys in Toll-like receptor 6 (TLR6), which affect TLR6 signaling. The affected children were also homozygous for three common, linked (r2 = 1) intronic single nucleotide variants (SNVs) in TLR6 (rs56245262, rs56083757 and rs7669329), that have previously shown association with KD in cohorts of European descent. Using transcriptome data from pre-treatment whole blood of KD subjects (n = 146), expression quantitative trait loci (eQTL) analyses were performed. Subjects homozygous for the intronic risk allele (A allele of TLR6 rs56245262) had differential expression of Interleukin-6 (IL-6) as a function of genotype (p = 0.0007) and a higher erythrocyte sedimentation rate at diagnosis. TLR6 plays an important role in pathogen-associated molecular pattern recognition, and sequence variations may affect binding affinities that in turn influence KD susceptibility. This integrative genomic approach illustrates how the analysis of WGS in multiplex families with a complex genetic disease allows examination of both the common disease–common variant and common disease–rare variant hypotheses.
Highlights
The ability to generate whole genome sequences (WGS) from individual subjects has existed for over a decade, the use of such methods to discover novel disease-causing variants in multiplexed families affected by complex genetic disease has been limited [1]
Since TLR2/6 activates the transcription factors, NFKB and AP1, we focused the expression quantitative trait loci (eQTL) analysis using only the 415 genes targeted by these transcription factors
The first analysis of WGS from an African Americans family with two siblings affected with Kawasaki disease (KD) revealed genetic variation in Toll-like receptor 6 (TLR6) that may be linked to the pro-inflammatory state during acute KD
Summary
The ability to generate whole genome sequences (WGS) from individual subjects has existed for over a decade, the use of such methods to discover novel disease-causing variants in multiplexed families affected by complex genetic disease has been limited [1]. Susceptibility to KD, the most common cause of acquired heart disease in children, is postulated to result from a complex set of genetic variants of which only a limited number have been validated to date [6]. This self-limited illness of unknown etiology presents with the sudden onset of fever and mucocutaneous signs and is associated with coronary artery vasculitis. Data from limited patient series suggests that African American is disproportionately affected by KD [14,15,16] Despite their apparent increased susceptibility, children of African American descent has been excluded from previous KD genetic analyses. The C allele of SNV rs28493229 in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 has been shown to affect gene transcription and impact intracellular calcium signaling and inflammasome activation [22, 28]
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