👤 Pamela Anna Burger

Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant neurodegenerative Polyglutamine (polyQ) disease, caused by a cytosine-adenine-guanine (CAG) repeat expansion in the ATXN3 gene, resulting in an expanded polyQ tract in the Ataxin-3 protein. Although the principal genetic determinant of the age at onset (AAO) in polyQ diseases is the expanded CAG repeat length, variability in AAO has been explained only partly, suggesting the existence of additional genetic modifiers. Apolipoprotein E (APOE) haplotypes are associated with the risk of numerous, especially degenerative, diseases. Investigations of a potential role of APOE haplotypes in AAO variability of SCA3 have resulted in partly conflicting outcomes, with current evidence lacking power and patient diversity. To further clarify a potential modifying effect of APOE haplotypes on the AAO in SCA3, over 800 SCA3 patients from different origins were enrolled in the present study. While we did not find an association of common APOE haplotypes or singular APOE alleles with AAO in SCA3, rare ε4 homozygosity was linked to an earlier AAO in individuals from Brazil, with a mean disease onset six years earlier than carriers of other APOE haplotypes. Our study thus provides initial evidence for a relevant impact of ε4 homozygosity on disease onset in SCA3 and provides evidence supporting an allele-dosage effect of APOE ε4 in polyQ diseases. Show less

The Koolen-de Vries syndrome (KdVS) is a multisystem disorder characterized by developmental delay, intellectual disability, characteristic facial features, epilepsy, cardiovascular and urogenital malformations, and various musculoskeletal disorders. Scoliosis is a common feature. The aim of this study is to fill the gap in the current knowledge about scoliosis in individuals with KdVS and to provide recommendations for management and follow-up. In total, 54 individuals with KdVS were included in the study, with a mean age of 13.6 years (range 1.9-38.8 years). Spine radiographs, MR scans, and corresponding radiology reports were analyzed retrospectively for scoliosis and additional anomalies. The presence of scoliosis-related clinical conditions was assessed in participants' medical records and by use of a parent survey. Scoliosis was present in 56% of the participants (30/54) with a mean age of onset of 10.6 years and curve progression during the growth spurt. Prevalence at age 6, 10, and 18 years was, respectively, 9%, 41%, and 65%. Most participants were diagnosed with a single curve (13/24, 54%), of which five participants had a long C-curve type scoliosis. No significant risk factors for development of scoliosis could be identified. Severity was mostly classified as mild, although 29% (7/24) of the curves were larger than 30° at last follow-up. Bracing therapy was received in 13% (7/54), and surgical spinal fusion was warranted in 6% (3/54). Remarkably, participants with scoliosis received less often physical therapy compared to participants without scoliosis (P = 0.002). Scoliosis in individuals with KdVS should be closely monitored and radiologic screening for scoliosis and vertebrae abnormalities is recommended at diagnosis of KdVS, and the age of 10 and 18 years. Show less

GenIDA is an international patient registry for individuals diagnosed with intellectual disability, autism spectrum disorder, and/or epilepsy, which is based on an online questionnaire that is completed by parent caregivers. In this study, the GenIDA data on Koolen-de Vries syndrome (KdVS) was analyzed illustrating the value of GenIDA and patient/caregiver participation in rare genetic neurodevelopmental disorders (NDDs). Recruitment was done on the GenIDA website from November 2016 to February 2022. Clinical information on individuals with KdVS was extracted for in-depth analysis and for comparison with the GenIDA data of individuals diagnosed with other NDDs. A total of 1417 patients/caregivers across 35 genetic conditions answered to the GenIDA questionnaire, including caregivers of 237 individuals with KdVS. GenIDA findings on KdVS were consistent with the existing literature, and there were no significant differences between individuals with a 17q21.31 microdeletion and those with a pathogenic variant in the GenIDA is a powerful registry to collect and harness valuable data on rare NDDs. The study shows that caregiver-driven data collection is effective in terms of global recruitment and centralization of clinical data. Show less

The coat color of dromedary is usually uniform and varies from black to white, although dark- to light-brown colors are the most common phenotypes. This project was designed to gain knowledge on novel color-related variants using genotyping-by-sequencing (GBS). The association between the SNPs and coat color was tested using MLM (mixed linear models) with kinship matrix. Three GWAS models including white color vs. non-white color, black vs. non-black color, and light-brown vs. dark-brown color were performed. There were no distinct genetic clusters detected based on the color phenotypes. However, admixture occurred among all individuals of the four different coat color groups. We identified nine significant SNPs associated with white color after Bonferroni correction, located close to Show less

Polyunsaturated fatty acids (PUFAs) have a major impact on human health. Recent genome-wide association studies (GWAS) have identified several genetic loci that are associated with plasma levels of n-3 and n-6 PUFAs in primarily subjects of European ancestry. However, the relevance of these findings has not been evaluated extensively in other ethnic groups. The primary aim of this study was to evaluate for genetic loci associated with n-3 and n-6 PUFAs and to validate the role of recently identified index loci using data from a Singaporean Chinese population. Using a GWAS approach, we evaluated associations with plasma concentrations of three n-3 PUFAs [alphalinolenic acid (ALA), eicosapentaenoic acid and docosahexaenoic acid], four n-6 PUFAs [linoleic acid (LA), gammalinolenic acid, dihomogammalinolenic acid (DGLA) and arachidonic acid], and estimates of delta-5 desaturase and delta-6 desaturase activities among the participants (N = 1361) of the Singaporean Chinese Health Study. Our results reveal robust genome-wide associations (p value <5 × 10(-8)) with ALA, all four n-6 PUFAs, and delta-6 desaturase activity at the FADS1/FADS2 locus. We further replicated the associations between common index variants at the NTAN1/PDXDC1 locus and n-6 PUFAs LA and DGLA, and between the JMJD1C locus and n-6 PUFA LA (p value between 0.0490 and 9.88 × 10(-4)). These associations were independent of dietary intake of PUFAs. In aggregate, we show that genetic loci that influence plasma concentrations of n-3 and n-6 PUFAs are shared across different ethnic groups. Show less