Neither maternal nor fetal mutation (E474Q) in the α-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome

Objective: An association between maternal HELLP syndrome and fetal long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been proposed. LCHAD catalyzes the third step in the β-oxidation of fatty acids in mitochondria. Whereas about 75% of LCHAD-deficient patients carry a G-to-C mutation at nucleotide position 1528 (Glu474Gln, E474Q) on both chromosomes, compound heterozygosity for E474Q on one chromosome and a second different LCHAD mutation on the other can be observed in up to 25% of LCHAD-deficiency cases; only very few patients carry two mutations different from E474Q. Genetic analysis of the mother alone is insufficient in case of compound heterozygosity. Since information on the fetal carrier status of the E474Q mutation in maternal HELLP syndrome is rare, we investigated the frequency of the E474Q mutation in families where the mother had HELLP syndrome. Methods: The occurrence of the E474Q mutation was analyzed by PCR and RFLP in 103 mothers with HELLP syndrome, in 82 children of affected pregnancies and in 21 fathers in families where fetal DNA was not available. In addition, 103 control women with only uncomplicated pregnancies were investigated. Results: The mutation E474Q was not detected in the study population. Conclusion: Neither maternal nor fetal heterozygosity for the E474Q mutation is a relevant factor of HELLP syndrom

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation