A Novel Homozygous Frameshift Variant in XYLT2 Causes Spondyloocular Syndrome in a Consanguineous Pakistani Family

We report on three new patients with spondyloocular syndrome (SOS) in a consanguineous Pakistani family. All three patients present progressive generalized osteoporosis, short stature, recurrent fractures, hearing loss and visual impairments. WES revealed a novel homozygous frameshift variant in exon 11 of XYLT2 (NG 012175.1, NP_071450.2) resulting in loss of evolutionary conserved amino acid sequences (840 - 865/865) at C -terminus p.R840fs*115. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients while the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. Only nine variants worldwide have previously been reported in XYLT2 in patients with SOS phenotype. These three patients with novel homozygous variant extend the genotypic and phenotypic spectrum of SOS.Peer reviewe

Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration

10.1194/jlr.M073684Journal of Lipid Research5891785-179

Lens status influences the association between CFH polymorphisms and age-related macular degeneration: Findings from two population-based studies in Singapore

10.1371/journal.pone.0119570PLoS ONE103e011957

Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease.

BACKGROUND: Global gene expression profiling can provide insight into the underlying pathophysiology of disease processes. Kawasaki disease (KD) is an acute, self-limited vasculitis whose etiology remains unknown. Although the clinical illness shares certain features with other pediatric infectious diseases, the occurrence of coronary artery aneurysms in 25% of untreated patients is unique to KD. METHODS: To gain further insight into the molecular mechanisms underlying KD, we investigated the acute and convalescent whole blood transcriptional profiles of 146 KD subjects and compared them with the transcriptional profiles of pediatric patients with confirmed bacterial or viral infection, and with healthy control children. We also investigated the transcript abundance in patients with different intravenous immunoglobulin treatment responses and different coronary artery outcomes. RESULTS: The overwhelming signature for acute KD involved signaling pathways of the innate immune system. Comparison with other acute pediatric infections highlighted the importance of pathways involved in cell motility including paxillin, relaxin, actin, integrins, and matrix metalloproteinases. Most importantly, the IL1β pathway was identified as a potential therapeutic target. CONCLUSION: Our study revealed the importance of the IL-1 signaling pathway and a prominent signature of innate immunity and cell migration in the acute phase of the illness

Association of Common SIX6 Polymorphisms With Peripapillary Retinal Nerve Fiber Layer Thickness: The Singapore Chinese Eye Study

PURPOSE. Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting. METHODS. Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip. RESULTS. A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 6 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 lm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P ¼ 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 lm in RNFL thickness (P ¼ 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 lm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 lm per risk allele, P ¼ 0.003), while the association did not reach significance in the nasal and temporal sectors. CONCLUSIONS. Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant

Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue

Background: A previous genome-wide association study identified 2 susceptibility loci for severe dengue at MICB rs3132468 and PLCE1 rs3740360 and further work showed these mutations to be also associated with less severe clinical presentations. The aim of this study was to determine if these specific loci were associated with laboratory features of dengue that correlate with clinical severity with the aim of elucidating the functional basis of these genetic variants. Methods: This was a case-only analysis of laboratory-confirmed dengue patients obtained from 2 prospective cohort studies and 1 randomised clinical trial in Vietnam (Trial registration: ISRCTN ISRCTN03147572. Registered 24th July 2012). 2742 dengue cases were successfully genotyped at MICB rs3132468 and PLCE1 rs3740360. Laboratory variables were compared between genotypes and stratified by DENV serotype. Results: The analysis showed no association between MICB and PLCE1 genotype and early viraemia level, platelet nadir, white cell count nadir, or maximum haematocrit in both overall analysis and in analysis stratified by serotype. Discussion: The lack of an association between genotype and viremia level may reflect the sampling procedures within the included studies. The study findings mean that the functional basis of these mutations remains unclear. Trial registration: ISRCTN ISRCTN03147572. Registered 24th July 2012